Adenosine receptor antagonists and methods of making and using the same

ABSTRACT

The invention is based on the discovery that compounds of Formula I are unexpectedly highly potent and selective inhibitors of the adenosine A 1  receptor. Adenosine A 1  antagonists can be useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable.  
     In one embodiment, the invention features a compound of formula 1:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. ProvisionalApplication Serial No. 60/165,191, filed on Nov. 12, 1999.

BACKGROUND OF THE INVENTION

[0002] The invention relates to antagonists of the adenosine receptorsand methods of making and using the same in the treatment of diseases.

[0003] Adenosine is an intracellular and extracellular messengergenerated by all cells in the body. It is also generated extracellularlyby enzymatic conversion. Adenosine binds to and activates seventransmembrane G-protein coupled receptors, eliciting a variety ofphysiological responses. Adenosine itself, substances that mimic theactions of adenosine (agonists), and substances that antagonize itsactions have important clinical applications. Adenosine receptors aredivided into four known subtypes (i.e., A₁, A_(2a), A_(2b), and A₃).These subtypes elicit unique and sometimes opposing effects. Activationof the adenosine A₁ receptor, for example, elicits an increase in renalvascular resistance while activation of the adenosine A_(2a) receptorelicits a decrease in renal vascular resistance.

[0004] In most organ systems, periods of metabolic stress result insignificant increases in the concentration of adenosine in the tissue.The heart, for instance, produces and releases adenosine to mediateadaptive responses to stress, such as reductions in heart rate andcoronary vasodilatation. Likewise, adenosine concentrations in kidneysincrease in response to hypoxia, metabolic stress and many nephrotoxicsubstances. The kidneys also produce adenosine constitutively. Thekidneys adjust the amount of constitutively produced adenosine in orderto regulate glomerular filtration and electrolyte reabsorption.Regarding control of glomerular filtration. activation of A₁ receptorsleads to constriction of afferent arterioles while activation of A_(2a)receptors leads to dilatation of efferent arterioles. Activation ofA_(2a) receptors may also exert vasodilatory effects on the afferentarteriole. Overall, the effect of activation of these glomerularadenosine receptors is to reduce glomerular filtration rate. Inaddition. A₁ adenosine receptors are located in the proximal tubule anddistal tubular sites. Activation of these receptors stimulates sodiumreabsorption from the tubular lumen. Accordingly, blocking the effectsof adenosine on these receptors will produce a rise in glomerularfiltration rate and an increase in sodium excretion.

SUMMARY OF THE INVENTION

[0005] The invention is based on the discovery that compounds of FormulaI are unexpectedly highly potent and selective inhibitors of particularsubtypes of adenosine receptors. Adenosine antagonists can be useful inthe prevention and/or treatment of numerous diseases, including cardiacand circulatory disorders, degenerative disorders of the central nervoussystem, respiratory disorders, and many diseases for which diuretictreatment is suitable.

[0006] In one embodiment, the invention features a compound of formulaI:

[0007] In formula I, R₁ and R₂ can, independently, be:

[0008] a) hydrogen;

[0009] b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of notless than 3 carbons (e.g., where the alkyl, alkenyl, or alkynyl can beunsubstituted or can be functionalized with one or more substituentsselected from hydroxy, alkoxy, amino, alkylamino, dialkylamino,heterocyclyl, acylamino, alkylsulfonylamino, andheterocyclylcarbonylamino; or

[0010] c) aryl or substituted aryl;

[0011] R₃ is selected from the group consisting of:

[0012] (a) a bicyclic, tricyclic or pentacyclic group selected from:

[0013] where the bicyclic or tricyclic group can be unsubstituted or canbe functionalized with one or more substitents selected from:

[0014] (a) alkyl, alkenyl, and alkynyl; where each alkyl, alkenyl, oralkynyl group can be unsubstituted or can be functionalized with one ormore substituents selected from the group consisting of(amino)(R₅)acylhydrazinylcarbonyl, (amino)(R₅)acyloxycarboxy,(hydroxy)(carboalkoxy)alkylcarbamoyl, acyloxy, aldehydo,alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylaminoalkylamino,alkylphosphono, alkylsulfonylamino, carbamoyl, R₅, R₅-alkoxy,R₅-alkylamino, cyano, cyanoalkylcarbamoyl, cycloalkylamino,dialkylamino, dialkylaminoalkylamino, dialkylphosphono,haloalkylsulfonylamino, heterocyclylalkylamino, heterocyclylcarbamoyl,hydroxy, hydroxyalkylsulfonylamino, oximino, phosphono, substitutedaralkylamino, substituted arylcarboxyalkoxycarbonyl, substitutedheteroarylsulfonylamino, substituted heterocyclyl, thiocarbamoyl, andtrifluoromethyl; or

[0015] (b) (alkoxycarbonyl)aralkylcarbamoyl, aldehydo, alkenoxy,alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylcarbamoyl,alkoxycarbonylamino, alkylsulfonylamino, alkylsulfonyloxy, amino,aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl,aminoalkylheterocyclylalkylcarbamoyl,aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl,aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino,arylsulfonyloxy, carbamoyl, carbonyl, —R₅, R₅-alkoxy,R₅-alkyl(alkyl)amino, R₅-alkylalkylcarbamoyl, R₅-alkylamino,R₅-alkylcarbamoyl, R₅-alkylsulfonyl, R₅-alkylsulfonylamino.R₅-alkylthio. R₅-heterocyclylcarbonyl, cyano, cycloalkylaminodialkylaminoalkylcarbamoyl, halogen, heterocyclyl,heterocyclylalkylamino, hydroxy, oximino, phosphate, substitutedaralkylamino, substituted heterocyclyl, substitutedheterocyclylsulfonylamino, sulfoxyacylamino, or thiocarbamoyl; and

[0016] (b) the tricyclic group:

[0017] where the tricyclic group is functionalized with one or moresubstitents selected from the croup consisting of:

[0018] (a) alkyl, alkenyl, and alkynyl; wherein each alkyl, alkenyl, oralkynyl group is either unsubstituted or functionalized with one or moresubstituents selected from the group consisting of(amino)(R₅)acylhydrazinylcarbonyl, (amino)(R₅)acyloxycarboxy,(hydroxy)(carboalkoxy)alkylcarbamoyl, acyloxy, aldehydo,alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylaminoalkylamino,alkylphosphono, alkylsulfonylamino, carbamoyl, R₅, R₅-alkoxy,R₅-alkylamino, cyano, cyanoalkylcarbamoyl, cycloalkylamino,dialkylamino, dialkylaminoalkylamino, dialkylphosphono,haloalkylsulfonylamino, heterocyclylalkylamino, heterocyclylcarbamoyl,hydroxy, hydroxyalkylsulfonylamino, oximino, phosphono, substitutedaralkylamino, substituted arylcarboxyalkoxycarbonyl, substitutedheteroarylsulfonylamino, substituted heterocyclyl, thiocarbamoyl, andtrifluoromethyl; and

[0019] (b) (alkoxycarbonyl)aralkylcarbamoyl, aldehydo, alkenoxy,alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylcarbamoyl,alkoxycarbonylamino, alkylsulfonylamino, alkylsulfonyloxy, amino,aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl,aminoalkylheterocyclylalkylcarbamoyl,aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl,aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino,arylsulfonyloxy, carbamoyl, carbonyl, —R₅, R₅-alkoxy,R₅-alkyl(alkyl)amino, R₅-alkylalkylcarbamoyl, R₅-alkylamino,R₅-alkylcarbamoyl, R₅-alkylsulfonyl, R₅-alkylsulfonylamino,R₅-alkylthio, R₅-heterocyclylcarbonyl, cyano, cycloalkylamino,diaikylaminoalkylcarbamoyl, halogen, heterocyclyl,heterocyclylalkylamino, oximino, phosphate, substituted aralkylamino,substituted heterocyclyl, substituted heterocyclylsulfonylamino,sulfoxyacylamino, and thiocarbamoyl;

[0020] R₄ can be hydrogen, C₁₋₄-alkyl, C₁₋₄-alkyl-CO₂H, or phenyl; wherethe C₁₋₄-alkyl, C₁₋₄-alkyl-CO₂H, and phenyl groups can be unsubstitutedor can be functionalized with one, two, three, or more substituents suchas halogen, —OH, —OMe, —NH₂, —NO₂, and benzyl, or benzyl functionalizedwith one, two, three, or more substituents such as halogen, —OH, —OMe.—NH₂, and —NO₂;

[0021] R₅ can be —CH₂COOH, —C(CF₃)₂OH, —CONHNHSO₂CF₃, —CONHOR₄,—CONHSO₂R₄, —CONHSO₂NHR₄, —C(OH)R₄PO₃H₂, —NHCOCF₃, —NHCONHSO₂R₄,—NHPO₃H₂, —NHSO₂R₄, —NHSO₂NHCOR₄, —OPO₃H₂, —OSO₃H, —PO(OH)R₄, —PO₃H₂,—SO₃H, —SO₂NHR₄, —SO₃NHCOR₄, —SO₃NHCONHCO₂R₄, or any of the following:

[0022]  X₁ and X₂ are chosen from oxygen (O) and sulfur(S).

[0023]  Z can be a single bond, —O—, —(CH₂)₁₋₃—, —O(CH₂)₁₋₂—, —CH₂OCH₂—,—(CH₂)₁₋₂O—, —CH═CHCH₂—, —CH═CH—, or —CH₂CH═CH—; and

[0024]  R₆ can be hydrogen, alkyl, acyl, alkylsufonyl, aralkyl,substituted aralkyl, substituted alkyl, or heterocyclyl.

[0025]  R₆ is preferably hydrogen. However, when R₆ is methyl or anothernon-hydrogen substituent, the compounds can be highly selective forinhibition of adenosine A_(2a) receptors.

[0026] In certain embodiments, R₁ and R₂ can be the same or differentalkyl groups (e.g., one or both can be n-propyl).

[0027] R₃ can be aralkyl substituted with —OH, —OMe, or -halogen;-methyl; or 3-hydroxypropyl, and Z can be a single bond.

[0028] In some embodiments, R₃ can be:

[0029] and can be unsubstituted or can be functionalized with one ormore (i.e., 1, 2, 3, or more) substituents such as hydroxy, R₅—, orR₅-alkenyl. Thus, the compound can be, for example,5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylicacid;8-(4-Hydroxy-bicyclo[3.2.1]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;or5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-2-carboxylicacid.

[0030] In other embodiments, R₃ can be:

[0031] and can be unsubstituted or can be functionalized with one ormore substituents such as hydroxy, R₅-alkyl, —R₅, R₅-alkenyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl,hydroxyalkyl, aldehydo, alkoxyalkyl, R₅-alkoxy, phosphate,R₅-alkylcarbamoyl, and R₅-alkyl(alkyl)carbamoyl. Thus, the compound canbe, for example, 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid;4-(2,6-Dioxo-1,3-dipiopyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde;4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester;3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid methyl ester;3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid methyl ester;3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid;3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid;4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-butyricacid; Phosphoric acidmono-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]ester;{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-methyl-amino}-aceticacid;{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-aceticacid;3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid;3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid methyl ester;3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid t-butyl ester; or3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-2-methyl-propionicacid.

[0032] In another embodiment, R₃ can be:

[0033] and can be unsubstituted or can be functionalized with one ormore substituents such as R₅-alkyl, -R₅, R₅-alkenyl, alkoxycarbonyl,alkoxycarbonylalkenyl, hydroxyalkyl, aldehydo, and hydroxy. Thus, thecompound can be, for example,6-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cubane-3-carboxylicacid;8-(6-Hydroxymethyl-cuban-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;or3-[6-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cuban-3-yl]-acrylicacid.

[0034] In yet another embodiment, R₃ can be:

[0035] and can be unsubstituted or can be functionalized with one ormore substituents such as R₅-alkyl, —R₅, R₅-alkenyl, R₅-alkoxy,alkoxycarbonyl, alkoxycarbonylalkenyl, hydroxyalkyl, aldehydo, andhydroxy. Thus, for example, the compound can be[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]non-1-yloxy]-aceticacid;8-(5-Hydroxy-bicyclo[3.2.2]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;or5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]nonane-1-carboxylicacid.

[0036] In still another embodiment, R₃ can be:

[0037] and can be unsubstituted or can be functionalized with one ormore substituents such as hydroxy, R₅-alkoxy, R₅-alkenyl,alkoxycarbonyl, and carbonyl. Thus, for example, the compound can be8-(4-Hydroxy-7-methyl-2,6-dioxa-bicyclo[3.3.1]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2.6-dione;or[1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-7-methyl-2,6-dioxa-bicyclo[3.3.1]non-4-yloxy]-aceticacid.

[0038] The compound can be, for example, in a form of an achiralcompound, a racemate, an optically active compound, a pure diastereomer,a mixture of diastereomers, or a pharmacologically acceptable additionsalt.

[0039] The compounds of this invention can also be modified by appendingappropriate functionalities to enhance selective biological properties.Such modifications are known in the art and include those that increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism, and/or alter rate of excretion. Examples of thesemodifications include, but are not limited to, esterification withpolyethylene glycols, derivatization with pivolates or fatty acidsubstituents, conversion to carbamates, hydroxylation of aromatic rings,and heteroatom-substitution in aromatic rings.

[0040] The invention also features a medicament composition includingany of the above compounds, alone or in a combination, together with asuitable excipient. The invention also features a method of treating asubject suffering from a condition characterized by an elevatedadenosine concentration and/or increased sensitivity to adenosine and/orelevated adenosine receptor number or coupling efficiency. The methodincludes the step of administering to the subject an amount of any ofthe above compounds to be effective as an adenosine receptor antagonist.The condition can be, for example, a cardiac and circulatory disorder, adegenerative disorder of the central nervous system, a respiratorydisorder, a disease for which diuretic treatment is indicated,hypertension, Parkinson's disease, depression, traumatic brain damage,post-stroke neurological deficit, respiratory depression, neonatal braintrauma, dyslexia, hyperactivity, cystic fibrosis, cirrhotic ascites,neonatal apnea, renal failure, diabetes, asthma, an edematous condition,congestive heart failure, or renal dysfunction (e.g., dysfunctionassociated with diuretic use in congestive heart failure, or renaltoxicity due to treatment with chemotherapeutic agents).

[0041] The invention also features a method of making 8-substitutedxanthines. The method includes the steps of obtaining aN7,C8-dihydroxanthine (e.g., compound 10 in FIG. 1), protecting the N7position of the xanthine (e.g., as a THP or BOM ether); deprotonatingthe C8 position with strong base (such as lithium diisopropylamide orn-butyl lithium) to generate an anion; trapping the anion with acarboxyl, carbonyl, aldehyde, or ketone compound; and deprotecting theprotected N7 position to obtain an 8-substituted xanthine.

[0042] As used herein, an “alkyl” group is a saturated aliphatichydrocarbon group. An alkyl group can be straight or branched, and canhave, for example, from 1 to 6 carbon atoms in a chain. Examples ofstraight chain alkyl groups include, but are not limited to, ethyl andbutyl. Examples of branched alkyl groups include, but are not limitedto, isopropyl and t-butyl.

[0043] An “alkenyl” group is an aliphatic carbon group that has at leastone double bond. An alkenyl group can be straight or branched, and canhave, for example, from 3 to 6 carbon atoms in a chain and 1 or 2 doublebonds. Examples of alkenyl groups include, but are not limited to, allyland isoprenyl.

[0044] An “alkynyl” group is an aliphatic carbon group that has at leastone triple bond. An alkynyl group can be straight or branched, and canhave, for example, from 3 to 6 carbon atoms in a chain and 1 to 2 triplebonds. Examples of alkynyl groups include, but are not limited to,propargyl and butynyl.

[0045] An “aryl” group is a phenyl or naphthyl group, or a derivativethereof. A “substituted aryl” group is an aryl group that is substitutedwith one or more substituents such as alkyl, alkoxy, amino, nitro,carboxy, carboalkoxy, cyano, alkylamino, dialkylamino, halo, hydroxy,hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl,sulfoxy, or carbamoyl.

[0046] An “aralkyl” group is an alkyl group that is substituted with anaryl group. An example of an aralkyl group is benzyl.

[0047] A “cycloalkyl” group is an aliphatic ring of, for example, 3 to 8carbon atoms. Examples of cycloalkyl groups include cyclopropyl andcyclohexyl.

[0048] An “acyl” group is a straight or branched alkyl-C(═O)— group or aformyl group. Examples of acyl groups include alkanoyl groups (e.g.,having from 1 to 6 carbon atoms in the alkyl group). Acetyl and pivaloylare examples of acyl groups. Acyl groups may be substituted orunsubstituted.

[0049] A “carbamoyl” group is a group having the structure H₂N—CO₂—.“Alkylcarbamoyl” and “dialkylcarbamoyl” refer to carbamoyl groups inwhich the nitrogen has one or two alkyl groups attached in place of thehydrogens, respectively. By analogy, “arylcarbamoyl” and“arylalkylcarbamoyl” groups include an aryl group in place of one of thehydrogens and, in the latter case, an alkyl group in place of the secondhydrogen.

[0050] A “carboxyl” group is a —COOH group.

[0051] An “alkoxy” group is an alkyl-O— group in which “alkyl” is aspreviously described.

[0052] An “alkoxyalkyl” group is an alkyl group as previously described,with a hydrogen replaced by an alkoxy group, as previously described.

[0053] A “halogen” or “halo” group is fluorine, chlorine, bromine oriodine.

[0054] A “heterocyclyl” group is a 5 to about 10 membered ringstructure, in which one or more of the atoms in the ring is an elementother than carbon, e.g., N, O, S. A heterocyclyl group can be aromaticor non-aromatic, i.e., can be saturated, or can be partially or fullyunsaturated. Examples of heterocyclyl groups include pyridyl,imidazolyl, furanyl, thienyl, thiazolyl, tetrahydrofuranyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, indolyl, indolinyl,isoindolinyl, piperidinyl, pyrimidinyl, piperazinyl, isoxazolyl,isoxazolidinyl, tetrazolyl, and benzimidazolyl.

[0055] A “substituted heterocyclyl” group is a heterocyclyl groupwherein one or more hydrogens are replaced by substituents such asalkoxy, alkylamino, dialkylamino, carbalkoxy, carbamoyl, cyano, halo,trihalomethyl, hydroxy, carbonyl, thiocarbonyl, hydroxyalkyl or nitro.

[0056] A “hydroxyalkyl” means an alkyl group substituted by a hydroxygroup.

[0057] A “sulfamoyl” group has the structure —S(O)₂NH₂. “Alkylsulfamoyl”and “dialkylsulfamoyl” refer to sulfamoyl groups in which the nitrogenhas one or two alkyl groups attached in place of the hydrogens,respectively. By analogy, “arylsulfamoyl” and “arylalkylsulfamoyl”groups include an aryl group in place of one of the hydrogens and, inthe latter case, an alkyl group in place of the second hydrogen.

[0058] An “antagonist” is a molecule that binds to a receptor withoutactivating the receptor. It competes with the endogenous ligand for thisbinding site and, thus, reduces the ability of the endogenous ligand tostimulate the receptor.

[0059] In the context of the present invention, a “selective antagonist”is an antagonist that binds to a specific subtype of adenosine receptorwith higher affinity than to other subtypes. The antagonists of theinvention can, for example, have high affinity for AI receptors or forA_(2a) receptors and are selective, having (a) nanomolar bindingaffinity for one of these two subtypes and (b) at least 10 times, morepreferably 50 times, and most preferably at least 100 times, greateraffinity for one subtype than for the other.

[0060] The invention provides numerous advantages. The compounds areeasily manufactured from readily available starting materials, in arelatively small number of steps. The compounds have a number ofvariable regions, allowing for systematic optimization. As specificantagonists, the compounds have broad medicinal utility. Since thecompounds are highly potent and specific antagonists, they can (1) beused in low doses to minimize the likelihood of side effects and (2) beincorporated into numerous dosage forms including, but not limited to,pills, tablets, capsules, aerosols, suppositories, liquid formulationsfor ingestion or injection, dietary supplements, or topicalpreparations. In addition to medical applications, the antagonistcompound can be used in the treatment of livestock and pet animals.

[0061] Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting. Otherfeatures and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0062]FIG. 1 is a series of illustrations of compounds of the invention.

[0063]FIG. 2 is a schematic representation of the synthesis of compoundsof the invention.

[0064]FIG. 3 is a schematic representation of an alternative route ofthe synthesis of compounds of the invention.

[0065]FIG. 4 is a schematic representation of the transformation ofcompound (VII) to the corresponding olefin (XII) via an alcohol (X).

[0066]FIG. 5 is a schematic representation of yet another route of thesynthesis of compounds of the invention.

[0067]FIG. 6 is a schematic representation of the synthesis of compound(XXI), which is the starting material used in the reaction shown in FIG.3.

[0068]FIG. 7 is a schematic representation of an alternative route ofthe synthesis of compound (XXI).

[0069]FIG. 8 is a schematic representation of the synthesis of variouscompounds of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] In general, the invention features highly potent and selectiveantagonists of the adenosine A₁ receptor. Selective antagonists of theadenosine A_(2a) receptor are also disclosed.

Synthesis of the Adenosine Antagonist Compounds

[0071] The compounds of the invention may be prepared by a number ofknown methods. Two general methods are described herein. Each of thememploys a common starting material, 1,3-disubstituted-5,6-diaminouracil(compound (VI)), as shown in the two schemes below.1,3-Disubstituted-5,6-diaminouracils can be prepared by treating thecorresponding symmetrically or unsymmetrically substituted urea withcyanoacetic acid, followed by nitrosation and reduction (see, e.g., J.Org. Chem. 16, 1879, 1951; Can J. Chem. 46,3413, 1968, incorporatedherein by reference). Unsymmetrically substituted xanthines can beaccessed via the method of Mueller (J. Med. Chem. 36, 3341, 1993,incorporated herein by reference). In this method, 6-aminouracil ismonoalkylated specifically at N3 of the uracil under Vorbruggenconditions. Alternatively, unsubstituted N1 or N3 position can befunctionalized (e.g., alkylation) in the last stage of synthesis.

[0072] In the first general method, a1,3-disubstituted-5,6-diaminouracil (compound (VI)) can first undergo aring closure reaction to produce a xanthine intermediate that isunsubstituted at the 8-position. This intermediate, in turn, can couplewith a precursor compound of the Z-R₃ moiety to produce the desired8-substituted xanthines. Referring to scheme 1 below, the startingmaterial 1,3-disubstituted-5,6-diaminouracil (i.e., compound (VI)) firstreacts with HC(OEt)₃ to undergo a ring closure reaction to produce axanthine intermediate that is unsubstituted at the 8-position (i.e.,compound (A)). This intermediate, after being protected by an aminoprotecting group (e.g., with THP or BOM at the N7 position), furtherundergoes a coupling reaction, in the presence of a strong base (e.g.,n-butyl-lithium (nBuLi) or lithium di-isopropyl-amide (LDA)), with aprecursor compound of the Z-R₃ moiety (e.g., an aldehyde or a ketone) toproduce an alcohol (i.e., compound (C)). The hydroxyl group of thealcohol can then be reacted to convert the alcohol to an amine, amercaptan, an ether, a lactone (e.g., compound (E)), or otherfunctionalized compound, by methods well known to those of ordinary,skill in the art. The N7 protection can then be removed to obtain adeprotected product (i.e., compound (F)), which can be furtherfunctionalized to yield compounds of this invention. See, e.g., Examples1-6, 51, and 52.

[0073] In the second general method, compounds of the invention can beprepared by reacting the starting material, a1,3-disubstituted-5.6-diaminouracil, with a precursor compound of theZ-R₃ moiety (e.g., aldehydes or carboxylic acids or carboxylic acidchlorides) to form a 6-amide substituted uracil intermediate, which inturn, can undergo a ring closure reaction to yield to a desired xanthinecompound. Referring to scheme 2 below, the starting material1,3-disubstituted-5,6-diaminouracil (i.e., compound (VI)) first coupleswith a di-carboxyl/ester-substituted precursor compound of the Z-R₃moiety, HOOC-Z-R₃-COOR_(a) (i.e., compound (G); R_(a) represents H, C₁₋₅alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3substituents selected from the group consisting of halo, hydroxyl, orC₁₋₃ alkoxy) to yield a 6-amide substituted uracil intermediate (i.e.,compound (H)) by reactions which are well known to one of ordinary skillin the art (e.g., by employing coupling reagents such asbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(BOP), O-benzo-triazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU), orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)). Examples of compound (G) includebicyclo[3.2.1]octane-1,5-dicarboxylic acid monomethyl ester andbicyclo[2.2.2]octane-1,4-dicarboxylic acid monoethyl ester. See, e.g.,Examples 8 and 13. The uracil intermediate can then undergo a ringclosure reaction in a basic condition (e.g., by employing KOH andisopropyl alcohol) to yield a xanthine compound (i.e., compound (J)),which can undergo further functionalization to produce various compoundsof the invention.

[0074] The desired aldehydes, ketones, carboxylic acids and carboxylicacid chlorides are commercially available (e.g., from Aldrich ChemicalCo.. Inc., %ilwaukee, Wis.) or can be readily prepared from commerciallyavailable materials by well-known synthetic methods. Such syntheticmethods include, but are not limited to, oxidation, reduction,hydrolysis, alkylation and Wittig homologation reactions. For referencesregarding the preparation of bicycloalkane carboxylic acids of theinvention (e.g., compound (III), which is an example of compound (G)),see, e.g., Aust. J. Chem. 38, 1705, 1985; Aust J. Chem. 39, 2061, 1986;J. Am. Chem. Soc. 75, 637, 1953; J. Am. Chem. Soc. 86, 5183, 1964; J.Am. Chem. Soc. 102, 6862, 1980; J. Org. Chem. 46, 4795, 198 1; and J.Org. Chem. 60, 6873, 1995.

[0075] In one instance, when compound (G) isbicyclo[2.2.2]octane-1,4-dicarboxylic acid or its corresponding esters(wherein Z is a single bond and R₃ is bicyclo[2.2.2]octyl), there are anumber of different methods for their preparation. Referring to FIG. 2,the starting material (i.e., compound (I)) is a1-COOR_(a)-4-COOR_(b)-cyclohexane, wherein each of R_(a) and R_(b),independently, represents H, C₁₋₅ alkyl, or benzyl, the phenyl ringbeing optionally substituted with 1-3 substituents selected from thegroup consisting of halo, hydroxyl, or C₁₋₃ alkoxy. Preferably, R_(a)and R_(b) are identical and represent methyl or ethyl. Three differentsynthetic routes are illustrated in FIG. 2 for the tranformation ofcompound (I) to compound (III) (an example of compound (G)). Route (1)(i.e., steps (A) and (B)) involves transforming compound (I) to itscorresponding chloroethyl-containing compound (II), which in turn,undergoes a ring closure reaction to form the corresponding1,4-bicyclo[2.2.2]octane acid/ester (III). See Examples 79 and 80. Route(2) also involves compound (II), which is transformed to compound (III)via another intermediate, compound (XXV), the iodoethyl-containingderivative of compound (I). See Examples 101 and 102. Route (3) (i.e.,step (TT)) involves the transformation of compound (I) to the1,4-bicyclo[2.2.2]octane acid/ester (III) without isolating theintermediates, i.e., compound (II). See Example 110.

[0076] To prepare compound (II), the starting material compound (I) istreated with about 1 to about 1.5 equivalents of a strong base. Strongbases that can be employed in this reaction include lithiumdiisopropylamide (LDA) and lithium isopropylcyclohexylamide, with LDAbeing the preferred base. Typical solvents for this reaction includetetrahydrofuran (THF), dimethoxyethane, dioxane, and t-butyl methylether, with THF being the preferred solvent. This reaction should beperformed in a temperature range of about −100° C. to about −60° C. Thereaction mixture is then treated with about 1 to about 1.5 equivalentsof bromochloroethane in the presence of at least four equivalents of areagent such as 1,1,3,3-tetramethylurea (TMU),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 15-crown-5,and 12-crown-4, with TMU being preferred. This reaction can be conductedin solvents such as THF, dimethoxyethane, dioxane, or t-butyl methylether (with THF being the preferred solvent) and at temperature rangingfrom about −80° C. to about 0° C. Ring closure reaction can be performedby first treating compound (II) with about four equivalents ofhexylmethylphosphoramide (HMPA), which is then followed by treatmentwith a strong base such as n-butyllithium and diisopropylamine (DIEA).

[0077] Turning to route (2), the chloroethyl-containing intermediate(II) can be treated with iodide to form the desired iodoethyl-containingintermediate (XXV). Examples of iodide that can be employed in thisreaction include sodium iodide, potassium iodide, lithium iodide, ortetrabutylammonium iodide, with NaI being the preferred iodide. Ringclosure reaction is then conducted in the presence of a suitable strongbase such as LDA or lithium isopropylcyclohexylamide (with LDA being thepreferred base) and reagents such as TMU or DMPU. Typical solvents foruse in this reaction include THF, dimethoxyethane, dioxane, or t-butylmethyl ether (with THF being preferred). This reaction should beconducted at a temperature ranging from about −80° C. to about 25° C.

[0078] Referring to route (3) in which the starting material compound(I) is converted directly to compound (III), compound (I) is firsttreated with about 1 to about 1.5 equivalents of a strong base such asLDA or lithium isopropylcyclohexylamide (with LDA being the preferredbase) in a suitable solvent such as THF, dimethoxyethane, dioxane,t-butyl methyl ether (with THF being the preferred solvent). Thetemperature of the reaction should range from about −100° C. to about−60° C. The resulting reaction mixture is then treated with less thanone equivalent of bromochloroethane in the presence of at least fourequivalents of HMPA at a temperature ranging from about −80° C. to about25° C. The resulting reaction mixture is further contacted with about 1to about 1.5 equivalents of a strong base such as LDA or lithiumisopropylcyclohexylamide (with LDA being the preferred base) and atleast four equivalents of HMPA in a suitable solvent such as THF,dimethoxyethane, dioxane, or t-butyl methyl ether (with THF being thepreferred solvent). This reaction should be conducted at a temperatureranging from about −100° C. to about −60° C. Note that no isolation ofintermediates are needed in route (3).

[0079] There are many methods to further functionalize compound (J),which contains a carboxylic acid or ester attached to the R₃ moiety. Forexample, compound (J) can be converted to the corresponding acrylic acidderivative. One way is to first hydrolyze the ester group of compound(J) (provided that R_(a) is not H) to give the corresponding carboxylicacid, reduce the carboxylic acid to the corresponding alcohol, oxidizethe alcohol to the corresponding aldehyde, and then perform aWadsworth-Horner-Emmons or Witting reaction to form the correspondingacrylic acid derivative. See, e.g., Examples 5, 6, 15, 16, and 17.Compound (J) can also be transformed directly to its correspondingalcohol (see, e.g., Example 4). A different variation is to transformcompound (J) directly to its corresponding aldehyde. A furthervariation, is to transform an ester-containing compound (J) to itscorresponding carboxylic acid, and then directly to the aldehyde.Alternatively, one can functionalize the precursor compound of the Z-R₃moiety before coupling to the or 1,3-disubstituted-8-unsubstitutedxanthine in scheme 1 or the 1,3-disubstituted-5,6-diaminouracil inscheme 2. Further, compounds of this invention can be prepared on solidsupport (e.g., Wang resin). See Example 36.

[0080]FIG. 3 discloses an alternative process to prepare compound (XIV)starting with compound (IV). The process illustrated in FIG. 2 employssimilar chemistry as illustrated in FIG. 2 but first prepares thepropionic acid side chain on the bicyclo[2.2.2]octyl moiety and thenadds on the 1,3-di-substituted uracil moiety followed by cyclization togive the desired compound (XIV). With regard to compound (XX), R₃ and R₄must be chemically different in their reactivity (e.g., methyl andbenzyl).

[0081]FIG. 4 discloses an alternative processes for the transformationof compound (VII) to the corresponding alcohol (X) and the subsequenttransformation of the alcohol (X) to the olefin (XII). Steps (F′) thru(H) are ring closure followed by saponification of the ester (VIII) tothe acid (IX) followed by reduction to the alcohol (X), see Examples 84,85, and 86. Alternatively, compound (VII) can undergo reduction (step(Y), see Example 103) and cyclization reactions to produce compound (X)(step (Z), see, e.g., Example 84a). A further alternative way involvessaponification and cyclization of compound (VII) to produce compound(IX) (steps (Y′) and (Z′)). These reactions are well known to thoseskilled in the art. See. e.g., Examples 85a and 84a. Steps (I) thru (DD)disclose alterntive processes for the transformation of the alcohol (X)to the corresponding olefin (XII). Specifically, steps (J). (AA) and(CC) (see Examples 89, 104, and 105) are alternative ways oftransforming the one carbon aldehyde of compound (XI) to the acrylicacid/ester-containing moiety by means known to those skilled in the art.

[0082] Referring to FIG. 5, compounds (XXIX) and (XXX) have beenpreviously described in the literature (Grob, C. A., Rich, R. Helv.Chim. Acta. 1979, 62, 2802; Ahmed, S. A., Hickmott, P. W. J. Chem. Soc.Perkin Trans. 1, 1979. 2180) (i.e., Steps (EE) and (FF)). Compound (XXX)can be converted to compound (XXXI) by well-known methods. For example,compound (XXX) may be reduced directly by means of a Wolff-Kishner orClemmenson reduction. Alternatively, the ketone functionality ofcompound (XXX) may first be converted to a dithioketal derivative, suchas for example, a 1,3-dithiane, 1,3-dithiolane or 1,3-dialkylthioketal.This intermediate, would, in turn, be desulfurized by Raney-Ni.Functional group manipulations of this sort are common and are known toone of average skill in the art. The following two steps, i.e., steps(GG) and (HH), represent examples of coupling a1,3-disubstituted-5,6-diaminouracil with a carboxylic acid followed bybase-mediated ring closure. In Step (II), the tertiary hydroxyl isconverted to its corresponding bromide, iodide ortrifluoromethanesulfonate by exposure to PBr₃, TMSBr, TMSI, KI andH₃PO₄, or trifluoromethanesulfonic anhydride in the presence of anon-nucleophilic base. Compound (XXXV) would then be formed by treatmentof (XXXIV) with a catalyst derived from a palladium salt (Pd(OAc)₂,PdCl₂, Pd(O₂CCF₃), etc.) and a phosphine ligand (PPh₃, P(o-tolyl)₃,etc.) followed by treatment with an olefin (such as methyl acrylate,methylpropiolate, etc.). Hydrogenation of compound (XXXV) followed byconversion of the ester to the corresponding acid would provide compound(XIV). Alternatively, the ester could first be converted to the acid andthe hydrogenation then performed to also generate (XIV).

[0083]FIG. 6 discloses a process to prepare acid (compound (XXI)) whichis the starting material for FIG. 3. In step (LL), treatment of compound(XXXI) with trifluoromethanesulfonic anhydride in the presence of a basesuch as pyridine affords XXXVI (R_(g)=OTf). The next step, i.e., step(MM), involves treating compound (XXXVI) (R_(g)=OTf) with a catalystderived from a palladium salt (Pd(OAc)₂, PdCl₂, Pd(O₂CCF₃)₂, etc.) and aphosphine ligand (PPh₃, P(o-tolyl)₃, etc.), which is then followed byexposure to an olefin (methyl acrylate, methyl propiolate, etc.) toafford compound (XXXVII) (wherein M=—C≡C— or —CH═CH—). In step (NN),compound (XXXVII) undergoes hydrogenation with palladium on carbon underan atmosphere of hydrogen to yield compound (XXI).

[0084] Turning to FIG. 7, compound (X) can be converted to compound (XL)containing a leaving group (LG) such as. e.g., halo (Cl, Br, or I),mesylate, nosylate, tosylate, and trifluoromethanesulfonate. The leavinggroup (LG) can then be displaced by a malonic ester, such as, e.g.,dimethyl malonate, in the presence of a base, such as, e.g., methoxide.The leaving group (LG) might also be displaced by Meldrum's acid, in thepresence of a base such as methoxide. Conversion of the esters or thecyclic anhydride, in the case of Meldrum's acid, to the correspondingacids followed by decarboxylation provides compound (XXXV).

[0085]FIG. 8 discloses an overview of the synthetic methods that can beemployed to produce various compounds of the invention. In step 1,treatment of compound 7-1 (Z=Br, I or OTf, and R═H,tetrahydropyran-2-yl- or 1-pyrollidinylmethyl) with a catalyst derivedfrom a palladium salt (Pd(OAc)₂, PdCl₂, Pd(O₂CCF₃)₂, etc.) and aphosphine ligand (PPh₃, P(o-tolyl)₃, etc.) is followed by exposure tocompound 7-2 (X═Li, ZnCl, MgBr, SnBu₃, B(OH)₂ and R′═CO₂H, CO₂Me, CO₂Et,C CCO₂Me, C CCO₂Et, CH═CHCO₂Me, CH═CHCO₂Et, CH₂CH₂CO₂Me, CH₂CH₂CO₂Et) toafford compound 7-3 (R═H, tetrahydropyran-2-yl- or 1-pyrollidinylmethyland R′═CO₂H, CO₂Me, CO₂Et, C≡CCO₂Me, C≡CCO₂Et, CH═CHCO₂Me, CH═CHCO₂Et,CH₂CH₂CO₂Me, CH₂CH₂CO₂Et). When R=tetrahydropyran-2-yl- or1-pyrollidinylmethyl treatment with acid (TFA, PPTS, HCl etc.) providescompound 7-3 where R═H. In step 2, treatment of compound 7-2 (Z=Br, I,or OTf, and R′═CO₂H, CO₂Me, CO₂Et, C≡CCO₂Me, C≡CCO₂Et, CH═CHCO₂Me,CH═CHCO₂Et, CH₂CH₂CO₂Me, CH₂CH₂CO₂Et) with a catalyst derived from apalladium salt (Pd(OAc)₂, PdCl₂, Pd(O₂CCF₃)₂, etc.) and a phosphineligand (PPh₃, P(O-tolyl)₃, etc.) is followed by exposure to compound 7-1(X═Li, ZnCl, MgBr, SnBu₃, B(OH)₂ and R=tetrahydropyran-2-yl- or1-pyrollidinylmethyl) to afford compound 7-3 (R=tetrahydropyran-2-yl- or1-pyrollidinylmethyl and R′═CO₂H, CO₂Me, CO₂Et, C≡CCO₂Me, C≡CCO₂Et,CH═CHCO₂Me, CH═CHCO₂Et, CH₂CH₂CO₂Me, CH₂CH₂CO₂Et). WhenR=tetrahydropyran-2-yl- or 1-pyrollidinylmethyl treatment with acid(TFA, PPTS, HCl etc.) provides compound 7-3 where R═H. Step 3 disclosesa HATU-mediated coupling reaction of diamino uracil moiety withbicyclo[2.2.2]octane acid (which has been described above). In step 4,treatment of compound 7-4 (X═Cl, Br, I) with a catalyst derived from apalladium salt (Pd(OAc)₂, PdCl₂, Pd(O₂CCF₃)₂, etc.) and a phosphineligand (PPh₃, P(o-tolyl)₃, etc.) is followed by exposure to an olefin(methyl acrylate, methyl propiolate, allyl alcohol, etc.) to affordcompound 7-5 (R′═C≡CCO₂Me, C≡CCO₂Et, CH═CHCO₂Me, CH═CHCO₂Et. CH₂CH₂CHO,etc). Step 5 discloses a base-promoted cyclization of uracil 7-5 to axanthine of type 7-3 (which has been described above). Similarly, thebase-promoted cyclization of uracil 7-4 to a xanthine of type 7-6 instep 6 has been described above. In step 7, treatment of compound 7-6(X═Cl, Br, I, OTf) with a catalyst derived from a palladium salt(Pd(OAc)₂, PdCl₂, Pd(O₂CCF₃)₂, etc.) and a phosphine ligand (PPh₃,P(o-tolyl)₃, etc.) is followed by exposure to an olefin (methylacrylate, methyl propiolate, allyl alcohol, etc.) to afford compound 7-3(R═H, R′═C≡CCO₂Me, C≡CCO₂Et, CH═CHCO₂Me, CH═CHCO₂Et, CH₂CH₂CHO, etc).Step 8 discloses oxidation of the terminal aldehyde group in compound7-3 (R═H, R′═CH₂CH₂CHO) which is accomplished by standard means (a.NaClO₂, NaH₂PO₄, 2-methyl-2-butene; b. NaIO4; etc.)

DEFINITIONS

[0086] All temperatures are in degrees Celsius (° C.).

[0087] TLC refers to thin-layer chromatography.

[0088] HPLC refers to high pressure liquid chromatography.

[0089] HMPA refers to hexylmethylphosphoramide.

[0090] THF refers to tetrahydrofuran.

[0091] THP refers to tetrahydropyranyl.

[0092] DMSO refers to dimethylsulfoxide.

[0093] DMF refers to dimethylformamide.

[0094] DDQ refers to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

[0095] DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0096] DBN refers to 1,5-diazabicyclo[4.3.0]non-5-ene.

[0097] DMAC refers to dimethylacetamide.

[0098] LDA refers to lithium diisopropylamide.

[0099] p-TSA refers to p-toluenesulfonic acid monohydrate.

[0100] NBS refers to N-bromosuccinimide.

[0101] NCS refers to N-chlorosuccinimide.

[0102] TEA refers to triethylamine.

[0103] BOC refers to t-butyl carbamate or tert-butoxycarbonyl.

[0104] Hunig's base refers to diisopropylethylamine,[(CH₃)₂CH]₂—N—CH₂CH₃.

[0105] DMAP refers to dimethylaminopyridine, (CH₃)₂N-pyridin-1-yl.

[0106] TFA refers to trifluoracetic acid. CF₃—COOH.

[0107] CDI refers to 1,1′-carbonyldiimidazole.

[0108] DIBAL refers to diisobutyl aluminum hydride.

[0109] THAM refers to tris(hydroxymethyl)aminomethane.

[0110] TMS refers to trimethylsilyl.

[0111] 15-crown-5 refers to 1,4,7,10,13-pentaoxacyclopentadecane.

[0112] 12-crown 4 refers to 1,4,7,10-tetraoxacyclododecane.

[0113] DMPU refers to 1,3-dimethyl-34,5,6-tetrahydro-2(1H)-pyrimidinone.

[0114] TMU refers to 1,1,3,3-tetramethylurea.

[0115] Saline refers to an aqueous saturated sodium chloride solution.

[0116] Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

[0117] IR refers to infrared spectroscopy.

[0118] FTIR refers to Fourier transform infrared spectroscopy.

[0119] ATR refers to attenuated total reflectance.

[0120] UV refers to ultraviolet spectroscopy.

[0121] NMR refers to nuclear (proton) magnetic resonance spectroscopy,chemical shifts are reported in ppm (d) downfield fromtetramethylsilane.

[0122] psi refers to pounds per square inch of pressure.

[0123] [a]_(D) ²⁵ refers to the angle of rotation of plane polarizedlight (specific optical rotation) fat 25° with the sodium D line (589A).

[0124] MS refers to mass spectrometry expressed as m/e, m/z ormass/charge unit. [M+H]⁺ refers to the positive ion of a parent plus ahydrogen atom. EI refers to electron impact. CI refers to chemicalionization. FAB refers to fast atom bombardment.

[0125] The phrase “pharmaceutically acceptable” refers to thoseproperties and/or substances which are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[0126] Pharmaceutically acceptable anion salts include salts of thefollowing acids methanesulfonic, hydrochloric, hydrobromic, sulfuric,phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic,CH₃—(CH₂)_(n)—COOH where n is 0 thru 4, HOOC—(CH₂)_(n)—COOH where n isas defined above.

[0127] When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

[0128] When the solubility of a solid in a solvent is used the ratio ofthe solid to the solvent is weight/volume (wt/v).

[0129] R_(a) is H, C₁₋₅ alkyl benzyl where the phenyl ring is optionallysubstituted with one to three halo, hydroxyl, or C₁₋₃ alkoxy.

[0130] R_(b) is H, C₁₋₅ alkyl, benzyl where the phenyl ring isoptionally substituted with one to three halo, hydroxyl, or C₁₋₃ alkoxy.When R_(a) and R_(b) are both present in the same molecule, they can bethe same or different.

[0131] R_(c) is H, C₁₋₅ alkyl, benzyl where the phenyl ring isoptionally substituted with one to three halo, hydroxyl, or C₁₋₃ alkoxy.When R_(a) and R_(c) are both present in the same molecule, they can bethe same or different.

[0132] R_(d) is H, C₁₋₅, benzyl where the phenyl ring is optionallysubstituted with one to three halo, hydroxyl, or C₁₋₃ alkoxy. When R_(c)and R_(d) are in the same molecule such as compound (XX) they must bedifferent. When R_(a) and R_(d) are both present in the same molecule,they must be different.

[0133] R_(e) is —H, C₁-C₅ alkyl, benzyl where the ring is optionallysubstituted with one to three halo, hydroxyl, or C₁₋₃ alkoxy. When R₁and R₅ are both present in the same molecule, they must be different.

[0134] R_(f) is —(CH₂)_(n)—CO—OR′ and —CH═CH—CO—OR′ where n is 0, 1, on2 and R′ is H or C₁₋₃ alkyl.

[0135] R_(g) is halo or triflate

[0136] M is —CH₂—CH₂— or —CH═CH—.

[0137] Tf refers to trifluoromethylsulfonyl, —SO₂—CF₃

[0138] LG refers to “Leaving Group” and is—O—SO₂-phenyl-NO_(2,)—O—SO₂—CH_(3,)—O—SO₂—phenyl-CH_(3,) or—O—SO₂—CF_(3.)

Uses for the Adenosine Antagonist Compounds

[0139] Activation of adenosine receptors elicits many physiologicalresponses, including reductions in renal blood flow, reductions inglomerular filtration rate, and increases in sodium reabsorption inkidney. Activation of adenosine receptors reduces heart rate, reducesconduction velocity, and reduces contractility. These, and the othereffects of activation of adenosine receptors in other organs, are normalregulatory processes. However, these effects become pathological in manydisease states. Thus, adenosine antagonists have extensive applicationin both prevention and treatment of disease. Diseases that can beprevented and/or treated with adenosine receptor antagonists include anyconditions (a) marked by the presence of an abnormal level of adenosineand/or (b) requiring for treatment the inhibition or stimulation ofadenosine production and/or release. Such conditions include, but arenot limited to, congestive heart failure, cardio-pulmonaryresuscitation, hemorrhagic shock, and other cardiac and circulatorydisorders; degenerative disorders of the central nervous system;respiratory disorders (e.g., bronchial asthma, allergic lung diseases);and many diseases for which diuretic treatment is indicated (e.g., acuteand chronic renal failure, renal insufficiency, hypertension).Degenerative illnesses such as Parkinson's disease, depression,traumatic brain damage, post-stroke neurological deficit, neonatal braintrauma, dyslexia, hyperactivity, and cystic fibrosis have all beenlinked to adenosine receptor activity. Other conditions in whichtreatment with adenosine receptor antagonists can have therapeuticutility include cirrhotic ascites, neonatal apnea, renal failureassociated with traditional diuretic therapy, diabetes, and asthma.

[0140] Additionally, applicants have discovered that the administrationof highly selective and potent adenosine A₁ receptor antagonists, forexample, can elicit a diuretic response when administered alone and canpotentiate the diuretic response to traditional diuretics. In addition,administration of adenosine receptor antagonists with traditionaldiuretics attenuate the reduction of glomerular filtration rate inducedby traditional diuretics. The claimed methods are applicable, forexample, in edematous conditions, such as congestive heart failure andascites.

Administration of the Adenosine Antagonist Compounds

[0141] The compounds can be administered to an animal (e.g., a mammalsuch as a human, non-human primate, horse, dog, cow, pig, sheep, goat,cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, ferret, lizard,reptile, or bird). The compounds can be administered in any mannersuitable for the administration of pharmaceutical compounds, including,but not limited to, pills, tablets, capsules, aerosols, suppositories,liquid formulations for ingestion or injection or for use as eye or eardrops, dietary supplements, and topical preparations. The compounds canbe administered orally, intranasally, transdermally, intradermally,vaginally, intraaurally, intraocularly, buccally, rectally,transmucosally, or via inhalation, implantation (e.g., surgically), orintravenous administration.

[0142] Optionally, the compounds can be administered in conjunction witha non-adenosine modifying pharmaceutical composition (e.g., incombination with a non-adenosine modifying diuretic as described, forexample, in co-pending application PCT/US99/08879 filed Apr. 23, 1999.incorporated herein by reference in its entirety).

[0143] The invention will be further described in the followingexamples, which do not limit the scope of the invention described in theclaims.

EXAMPLES Example 18-(3-Oxo-2-oxa-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0144]1,3-Dipropyl-7-(tetrahydropyran-2-yl)-3,7-dihydro-purine-2,6-dione (3.0g, 9.37 mmol) was dissolved in 100 ml of anhydrous THF and cooled to −78° C. nBuLi (2.5 M in hexanes, 4.70 ml) was added, followed by4-oxo-cyclohexanecarboxylic acid ethyl ester (9.37 mmol, 1.5 ml) and thereaction mixture was slowly warmed to RT and stirred at RT overnight.The next day, the reaction was quenched with sat'd. aq. NH₄Cl. Thereaction was diluted with water and extracted with EtOAc. The organiclayer was dried and concentrated under reduced pressure. Purification bychromatography (2:1 hex/EtOAc) afforded 1.30 g of the desired alcoholderivative.

[0145] This product (290 mg, 0.592 mmol) was dissolved in 3 ml of THFand an aq. solution of LiOH (2M, 0.60 ml) was added. The reactionmixture was stirred at RT for 18 h. It was then quenched with 10% aq.citric acid and extracted with EtOAc. The organic layer was dried(Na₂SO₄) and concentrated.

[0146] The resulting acid was dissolved in of acetic anhydride (3 ml)and refluxed for 1 h. It was then cooled to RT and concentrated. Theresulting residue was dissolved in EtOAc and washed with sat'd. aq.NaHCO₃, brine, dried (Na₂SO₄), and concentrated. Purification bychromatography (2:1 EtOAc/hex) afforded the title compound. MS (ES⁺)361.

Example 28-(2-Oxa-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0147]4-[2,6-dioxo-1,3-dipropyl-7-(tetrahydropyran-2-yl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-4-hydroxy-cyclohexanecarboxylicacid ethyl ester (Example 1) (270 mg, 0.551 mmol) was dissolved in 4 mlof anhydrous THF, and LiBH₄ (2.0 M solution in THF, 0.55 ml) was added.The reaction mixture was stirred at RT overnight. The next day, thereaction was quenched with 10% aq. citric acid and extracted with EtOAc.The organic layer was concentrated under reduced pressure and theresulting crude product was purified by chromatography (1:1 hex/EtOAc).

[0148] The pure diol (90 mg, 0.201 mmol) was dissolved in CH₂Cl₂ (5 ml)and Et₃N (1.2 eq) was added. This was then followed by addition of MsCl(1.1 eq). The reaction was stirred at RT for 1 h and then quenched withsat'd. aq. NH₄Cl and extracted with CH₂Cl₂. The organic layer was dried(Na₂SO₄) and concentrated.

[0149] The resulting residue was dissolved in THF (2 ml) and 1 N HCl (1ml). The reaction mixture was stirred at RT for 12 h and diluted withH₂O and extracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by HPLC using aq.CH₃CN afforded the title compound. MS(ES⁺) 347.

Example 3 Acetic acid1-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-4-ylmethylester

[0150] 4-Oxo-cyclohexanecarboxylic acid ethyl ester was converted to thecorresponding ketal derivative according to an established procedure(Greene, Protective Groups in Organic Synthesis, Third Edition). Thisketal derivative (1.0 g, 4.67 mmol) was dissolved in anhydrous THF (15ml). In a separate flask, 2,2,6,6-tetramethylpiperidine (1.2 ml, 1.5 eq)was dissolved in of THF (30 ml) and cooled to −78° C. and nBuLi (2.80ml, 2.5 M solution in hexanes, 1.5 eq) was added. After 15 min, theketal solution was added and the reaction mixture was stirred at −78° C.for 1 h. Methyl chloroformate (0.72 ml, 2 eq) was added and the reactionmixture was warmed to RT. The reaction was quenched with sat'd. aq.NH₄Cl and extracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by chromatography (2:1hex/EtOAc) afforded the diester intermediate.

[0151] This diester (8.0 g, 29.4 mmol) was dissolved in dry Et₂O (500ml) and cooled to 0° C. LiAlH₄ (2.2 g, 2 eq) was added in small portionsover a period of 15 min. The reaction mixture was stirred at 0° C. for15 min and then warmed to RT and stirred for 1 h. It was then cooled to0° C. and carefully quenched with of 5% aq. NaOH (10 ml). The mixturewas filtered and the filtrate was concentrated to afford 3.30 g of diolintermediate.

[0152] This diol (1.60 g, 7.9 mmol) was dissolved in pyridine (10 ml)and TsCl (3.3 g, 2.2 eq) was added. The reaction mixture was stirred atRT for 18 h. It was then diluted with EtOAc and washed with 10% aq.citric acid. The organic layer was dried (Na₂SO₄) and concentrated toafford the ditosylate derivative.

[0153] This material was dissolved in THF (60 ml) and of 1 N HCl (30ml). The reaction mixture was stirred under reflux for 1 h. The reactionmixture was cooled to RT and extracted with EtOAc. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. Purification bychromatography (1:1 hex/EtOAc) afforded 2.0 g of the ditosylatederivative of 4,4-bis-hydroxymethyl-cyclohexanone.

[0154]1,3-Dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dione(5.30 g, 16.5 mmol) was dissolved in anhydrous THF (250 ml) and cooledto −78 ° C. nBuLi (2.5 M in hexanes, 6.60 ml. 1 eq) was added, followedby the ditosylate derivative of 4,4-bis-hydroxymethyl-cyclohexanone (7.7g, 1 eq) and the reaction mixture was slowly warmed to RT and stirred atRT overnight. The next day, the reaction was quenched with sat'd. aq.NH₄Cl. The reaction was diluted with water and extracted with EtOAc. Theorganic layer was dried and concentrated under reduced pressure.Purification by chromatography (2:1 hex/EtOAc) afforded 10.4 g of theditosylate xanthine derivative.

[0155] This intermediate (9.0 g) was dissolved in dry THF (200 ml) andpowdered NaOH (9.0 g) was added. The reaction mixture was stirred underreflux for 24 h. It was then cooled to RT and diluted with H₂O andextracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by chromatography (2:1hex/EtOAc) afforded 5.6 g of the monotosylate derivative.

[0156] This monotosylate derivative (4.0 g, 6.5 mmol) was dissolved inDMSO(70 ml). NaOAc (9 g) was added and the reaction mixture was stirredat 70-80° C. for 2 days. The reaction mixture was cooled to RT anddiluted with H₂O and extracted with EtOAc. The organic layer was dried(Na₂SO₄) and concentrated. Purification by chromatography (2:1hex/EtOAc) afforded 800 mg of the title compound. MS (ES⁺) 419.

Example 48-(4-Hydroxymethyl-2-oxa-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0157] Acetic acid1-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-4-ylmethylester was prepared as described in Example 3. This acetate derivative(120 mg, 0.287 mmol) was dissolved in MeOH (5 ml). K₂CO₃ (200 mg, 5 eq)was added as a solution in 5 ml of H₂O. The reaction mixture was stirredat RT. for 2 h. The reaction mixture was diluted with H₂O and extractedwith EtOAc. The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure. The resulting residue was purified by preparative HPLCusing aq CH₃CN to afford the title compound. MS(ES⁺) 377.

Example 51-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxabicyclo-[2.2.2]octane-4-carboxylicacid

[0158] Acetic acid1-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-4-ylmethyl ester was prepared as described in Example 3. This acetatederivative (400 mg) was dissolved in 3 ml of CH₂Cl₂ and 3 ml ofdihydropyran. PPTS (10 mg) was added and the reaction mixture wasstirred at RT for 18 h. The reaction mixture was diluted with CH₂Cl₂ andwashed with NaHCO₃, 5% aq. citric acid and brine. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure.

[0159] The resulting residue was dissolved in 10 ml of MeOH and K₂CO₃(450 mg) was added as a solution in 10 ml of H₂O. The resulting reactionmixture was stirred at RT, for 18 h. It was then diluted with H₂O andextracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated to afford the alcohol derivative,8-(4-hydroxymethyl-2-oxa-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dione.

[0160] This material (320 mg, 0.7 mmol) was dissolved in 8 ml of DMF.PDC (1.0 g, 4 eq) was added and the reaction mixture was stirred at RTfor 18 h. The reaction mixture was diluted with 3 ml of 10% aq citricacid and 20 ml of H₂O and quickly extracted with EtOAc. The organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was dissolved in 10 ml of H₂O and 20 ml of CH₃CN along with 1 mlof TFA. The reaction mixture was stirred at RT for 18 h. The reactionmixture was concentrated. The resulting residue was purified bypreparative HPLC using aq. CH₃CN to afford the title compound. MS (ES⁺)391.

Example 63-[1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo-[2.2.2]oct-4-yl]-acrylicacid

[0161] 8-(4-Hydroxymethyl-2-oxa-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dionewas synthesized according to the procedure outlined in EXAMPLE 4. Thisalcohol derivative (140 mg, 0.3 mmol) was dissolved in 5 ml of CH₂Cl₂along with the Dess-Martin reagent (Lancaster, 155 mg, 1.2 eq). Thereaction mixture was stirred at RT for 1 h. The reaction mixture wasdiluted with aq sodium sulfite (1 M) and extracted with CH₂Cl₂. Theorganic layer was dried (Na₂SO₄) and concentrated under reduced pressureto afford the aldehyde intermediate.

[0162] This material was immediately dissolved in 4 ml of anhydrous THF.In a separate flask, trimethylphosphonoacetate (60 μL, 1.2 eq) wasdissolved in 3 ml of anhydrous THF and cooled to 0° C. and KHDMS (0.5 Min PhMe, 730 μL) was added. This mixture was stirred at 0° C. for 10 minand then added to the solution of the aldehyde. The reaction mixture wasstirred at RT for 3 h and then quenched with sat'd. aq. NH₄Cl andextracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated.

[0163] The resulting residue was dissolved in 4 ml of THF and 4 ml ofH₂O containing LiOH (4 eq) and stirred at RT for 18 h. The reactionmixture was diluted with aq. citric acid and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄) and concentrated. Purification bypreparative HPLC using aq. CH₃CN afforded the titled compound. MS (ES⁺)417.

Example 73-[1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo-[2.2.2]oct-4-yl]-propionicacid

[0164]3-[1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acrylicacid was dissolved in 50 ml of MeOH. 10% Pd on C (10 mg) was added andthe reaction mixture was hydrogenated at RT under 55 psi of H₂ for 30min. The reaction mixture was filtered through a pad of Celite and thefiltrate was concentrated under reduced pressure to afford the titlecompound. MS (ES⁺) 419.

Example 85-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylicacid

[0165] To a solution of bicyclo[3.2.1]octane-1,5-dicarboxylic acidmonomethyl ester (Della, E. W.; Tsanaktsidis, J. Aust. J. Chem. 1985,38, 1705; Della, E. W.; Tsanaktsidis. J. Aust. J. Chem. 1986, 39, 2061);(5.94 mmol, 1.26 g), HATU (5.94 mmol, 2.26 g), and5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (Daly, J.W. et al., J. Med. Chem., 1985, 28 (4), 487) (5.94 mmol, 1.56 g) in DMF(25 ml) was added iPr₂NEt (17.82 mmol, 3.1 ml). The reaction was stirredovernight at RT. It was concentrated at the pump to remove DMF. Theresidue was dissolved in EtOAc and washed with 1N HCl, 5% NaHCO₃, andbrine. and dried (MgSO₄). Filtration and evaporation followed by flashcolumn chromatography, eluting with 3:1 EtOAc/hexanes provided product(0.7 g. 28%) as an oil. MS (ES⁺) 443.1 (M+Na, 100%), 421.4 (M+H, 10%).

[0166] A solution of5-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[3.2.1]octane-1-carboxylicacid ethyl ester (0.238 mmol, 0.10 g) in 20% NaOH (2.0 ml) and MeOH(10.0 ml) was stirred and refluxed 5 h. The reaction was cooled to roomtemperature and then concentrated to remove MeOH. The aqueous wasacidified (pH 2-3) with conc. HCl and then extracted with EtOAc. Thecombined EtOAc extracts were washed with H₂O and brine, and dried(MgSO₄). Filtration and evaporation followed by reverse phase HPLCprovided product (0.039 g, 42%) as a solid.

[0167] MS (ES⁺) 389.12 (M+H, 100%)

Example 98-(4-Hydroxy-2,6-dioxa-tricyclo[3.3.1.0^(3,7)]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0168] A solution of LDA was prepared at −78° C. by addition of n-BuLi(1.8 M in hexanes. 1.7 ml) to a solution of iPr₂NH (3.61 mmol, 0.506 ml)in THF (25 ml). After addition, the LDA was aged at −78° C. for 45 min.To this was added slowly at −78° C a solution of1,3-dipropyl-7-(tetrahydropyran-2-yl)-3,7-dihydropurine-2,6-dione(Example 52) (2.78 mmol, 0.89 g) in THF (35 ml). After stirring another1 h at −78° C., a solution of 8-oxa-bicyclo[3.2.1]oct-6-en-3-one (Mann,J. et al., J. Chem. Soc. Perkin Trans I 1992, 787) (2.78 mmol. 0.345 g)in THF (5 ml) was added. The reaction was stirred overnight with warmingto room temperature. It was quenched by addition of saturated NH₄Cl andextracted with EtOAc. The combined organic extracts were washed withsaturated NH₄Cl, H₂O and brine, and dried (MgSO₄). Filtration andevaporation followed by flash column chromatography, eluting with anEtOAc/CH₂Cl₂ gradient provided the coupled product (0.55 g, 45%). MS(ESP+, 60V): 445.07 (M+H,. 35%). 361.06 (48%), 343.05 (100%).

[0169] To a solution of8-(3-hydroxy-8-oxa-bicyclo[3.2.1]oct-6-en-3-yl)-1,3-dipropyl-7-(tetrahydropyran-2-yl)-3,7-dihydropurine-2,6-dione(prepared as described above) (0.225 mmol, 0.10 g) in iPrOH (2 ml) andH₂O (1 ml) was added MMPP (80%, 0.45 mmol, 0.223 g) in one portion.After 5 d at room temperature, the reaction was quenched by addition ofsat'd. aq. Na₂S₂O₃ and concentrated to remove iPrOH. The aqueous residuewas partitioned between EtOAc and sat'd. NaHCO₃. The organic extractswere washed with H₂O and brine, and dried (MgSO₄). Filtration andevaporation provided product (0.093 g, 90%) as a foam.

[0170]³C NMR (75 MHz, CDCl₃): 11.50, 11.63, 21.55, 21.61, 21.72, 23.00,25.01, 32.17, 37.96, 40.42, 43.52, 45.19, 54.46, 54.62, 70.46, 70.79,71.51, 71.64, 86.09, 107.18, 147.34, 151.21, 155.19, 157.82.

[0171] To a solution of8-(4-hydroxy-2,6-dioxa-tricyclo[3.3.1.0^(3,7)]non-1-yl)-1,3-dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dione(0.065 mmol, 0.030 g) in 1:1 THF/MeOH (6 ml) was added 1N HCl (3 drops).The reaction was stirred at room temperature 4 h and then concentratedto dryness. The residue was purified by reverse phase HPLC, providingproduct (0.0094 g, 38%). ¹H NMR (400 MHz, d6-DMSO): 0.80-0.89 (m, 6H),1.48-1.56 (m, 2H), 1.60-1.70 (m, 2H), 1.9-2.09 (m, 2H), 2.2-2.25 (m,1H), 3.78-3.82 (m, 2H), 3.89-3.91 (m, 2H), 3.99 (s, 1H), 4.21(br s, 1H),4.51 (br s, 1H), 4.80 (m, 1H).

Example 108-(5-Hydroxymethyl-bicyclo[3.2.1]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0172] To a solution of5-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[3.2.1]octane-1-carboxylicacid methyl ester (prepared as described for Example 8) (0.714 mmol,0.30 g) was added LiBH₄ (2M in THF, 0.54 ml). After stirring overnightat room temperature and then at reflux 90 min. The reaction was quenchedat room temperature by addition of 1N HCl, diluted with H₂O andextracted with EtOAc. The combined organics were washed with saturatedNaHCO₃, H₂O, and brine, and dried (MgSO₄). Filtration and evaporationprovided product (0.20 g, 71%) as an oil. MS (ES⁺) 415.15 (M+Na. 100%),393.5 (M+H. 48%)

[0173] A solution of 5-hydroxymethyl-bicyclo[3.2.1]octane-1-carboxylicacid(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide(0.51 mmol, 0.20 g) in 20% NaOH (2.0 ml) and MeOH (10.0 ml) was stirredand refluxed overnight. The reaction was cooled to room temperature andthen concentrated to remove MeOH. The aqueous was acidified (pH 2-3)with conc. HCl and then extracted with EtOAc. The combined EtOAcextracts were washed with saturated NaHCO₃, H₂O and brine, and dried(MgSO₄). Filtration and evaporation followed by flash chromatographyeluting with 3:2 EtOAc/CH₂Cl₂ provided title compound (0.077 g, 40%) asan oil. ¹³C NMR (100 MHz, CDCl₃): 11.53 (q), 11.74 (q), 20.26 (t), 21.71(t), 31.62 (t), 34.15 (t), 37.29 (t), 43.49 (s), 45.54 (t), 45.67 (t),46.14 (t), 46.90 (t), 70.51 (t), 71.11 (s), 107.03 (s), 149.25 (s),151.54 (s), 155.88 (s), 162.58 (s).

Example 11[1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2,6-dioxa-tricyclo-[3.3.1.0^(3,7)]non-4-yloxy]-aceticacid

[0174] To a solution of8-(4-hydroxy-2,6-dioxa-tricyclo[3.3.1.0^(3,7)]non-1-yl)-1,3-dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dione(Example 9) (0.065 mmol, 0.030 g) in THF (2 ml) was added NaH (60%dispersion, 0.068 mmol, 0.0027 g) in one portion. The reaction wasstirred at room temperature 1 h, and then t-butyl bromoacetate (0.068mmol. 10 μL) was added. After 3 d, the reaction was quenched withsaturated NH₄Cl and extracted with EtOAc (3×). The combined organicswere washed with brine and dried (MgSO₄). Filtration and evaporationyielded product (0.059 g) contaminated with t-butyl bromoacetate. MS(ES⁺) 575.15 (M+H).

[0175] A solution of{1-[2,6-dioxo-1,3-dipropyl-7-(tetrahydropyran-2-yl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-2,6-dioxa-tricyclo[3.3.1.0^(3,7)]non-4-yloxy}-aceticacid tert-butyl ester (0.10 mmol, 0.059 g) in CH₂Cl₂ (1 ml) was treatedwith TFA (1 ml) and stirred at room temperature overnight. The reactionwas concentrated to dryness and the residue purified by reverse phaseHPLC to provide product (0.0036 g, 8%). MS (ES⁺) 435.13 (M+H).

Example 123-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]oct-1-yl]-acrylicacid

[0176] To a solution of5-(2,6-dioxo-1,3-dipropyl-2,3,6.7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylicacid (Example 8) (1.29 mmol. 0.50 g), HATU (1.29 mmol. 0.49 g), andN,O-dimethylhydroxylamine hydrochloride (1.29 mmol. 0.126 g) in DMF (12ml) was added iPr₂NEt (3.86 mmol, 0.67 ml). The reaction was stirredovernight at RT. It was concentrated at the pump to remove DMF. Theresidue was dissolved in EtOAc and washed with 1N HCl. sat'd. NaHCO₃,and brine, and dried (MgSO₄). Filtration and evaporation providedproduct (0.791 g) contaminated with DMF. MS (ES⁺) 432.13 (M+H)

[0177] To a solution of5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylicacid methoxy-methyl-amide (0.232 mmol, 0.100 g) in THF (3 ml) at −78° C.was added a solution of LiAlH₄ (1M in THF, 0.52 ml). After addition,reaction was stirred at −78° C. 30 min. then at 0C 30 min. The reactionwas quenched carefully by the sequential addition of H₂O (20 μL), 20%NaOH (20 μL) and H₂O (40 μL). The suspension was stirred brisklyovernight, then filtered through Celite, rinsing the flask and cakegenerously with THF. Evaporation followed by flash chromatography,eluting with 5% THF/CH₂Cl₂ provided product (0.048 g, 56%) as an oil. MS(ES⁺): 373.17 (M+H).

[0178] To a solution of trimethyl phosphonoacetate (0.310 mmol, 0.056 g)in THF (4 ml) at 0° C. was added a solution of KHMDS (0.5 M in PhMe, 0.6ml). After stirring 45 min, a solution of5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]octane-1-carbaldehyde(0.129 mmol, 0.048 g) in THF (2 ml) was added slowly. After stirringovernight at room temperature, the reaction was quenched with saturatedNH₄Cl and extracted with EtOAc. The combined organics were washed withsaturated NaHCO₃, brine, and dried (MgSO₄). Filtration and evaporationyielded product (0.119 g) contaminated with excess trimethylphosphonoacetate. MS (ES⁺) 429.16 (M+H)

[0179] A solution of3-[5-(2,6-dioxo-1.3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]oct-1-yl]-acrylicacid methyl ester (0.129 mmol, 0.055 g) in THF (4 ml) was treated atroom temperature with 1N LiOH (1.1 ml). The reaction was heatedovernight at reflux. The reaction was cooled to room temperature,diluted with H₂O, acidified with conc. HCl (pH 2-3) and extracted withEtOAc. The combined organics were washed with brine and dried (MgSO₄).Filtration and evaporation followed by reverse phase HPLC provided pureproduct (0.010 g, 19%). MS (ES⁺) 397.24 (M+H−OH, 100%); MS (ES⁻) 413.01(M−H, 100%)

Example 134-(,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid.

[0180] To a stirred mixture of 2.00 g (8.84 mmol) ofbicyclo[2.2.2]octane-1,4-dicarboxylic acid monoethyl ester, 2.60 g (9.89mmol) of 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride,5.32 ml (38.1 mmol) of NEt₃, and 30 ml anhydrous acetonitrile was added3.76 g (9.89 mmol) of HATU. The reaction solution was stirred at rt for1 h. The reaction mixture was concentrated in vacuo and combined with 40ml EtOAc and 40 ml of 10% citric acid. The aqueous layer was separatedand washed twice with 40-ml portions of EtOAc. The combined organicfractions were washed with 20-ml portions of sat'd NaHCO₃ and brine andconc'd in vacuo. The resultant solid was combined, in a 200-mlround-bottom flask equipped with a condenser, with a mixture of 35 ml ofi-PrOH and 35 ml of 1 N KOH (35 mmol) and heated to reflux. Afterheating for 1 hour, the reaction solution was conc'd in vacuo, taken upin 40 ml of water, and washed twice with 30-ml portions of CH₂Cl₂. Theaqueous layer was acidified with conc'd HCl and the resultantprecipitate collected by suction filtration to give 3.00 g (87% yield)of an off-white solid. (MH⁺=389.25)

[0181] The following compounds were made in an analogous manner.

Example 13a8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0182] (MH⁺=361.15)

Example 13b8-(4-Pentyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0183] (MH⁺=415.19)

Example 13c5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]nonane-1-carboxylicacid

[0184] (MH⁺=403.30)

Example 13d[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-carbamicacid methyl ester

[0185] (MH⁺=418.15)

Example 13e8-(4-Bromo-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0186] (MNa⁺=425.22)

Example 13f8-(1-Aza-bicyclo[2.2.2]oct-4-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0187] (MH⁺=346.31)

[0188] N-3 alkylations of the precursor monopropyl uracils wereperformed by literature procedures (Müller, C. E.; Geis. U.; Hipp, J.;Schobert, U.; Frobenius, W.; Pawlowski, N.; Suzuki, F.;Sandoval-Ramirez, J. J. Med. Chem. 1997, 40, 4396-4405.) on BOCprotected 5,6-diamino-1-propyl uracil with subsequent BOC removal from4N HCl in dioxane. The above coupling-cyclization protocol was thenemployed to make xanthine derivatives.

Example 13g3-(2-Methoxy-ethyl)-8-(4-pentyl-bicyclo[2.2.2]oct-1-yl)-1-propyl-3,7-dihydro-purine-2,6-dione

[0189] (MH⁺=431.64)

Example 13h4-[3-(2-Methoxy-ethyl)-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.2.2]octane-1-carboxylicacid

[0190] (MH⁺=405.63)

Example 13i3-[2-(4-Methoxy-phenyl)-ethyl]-8-(4-pentyl-bicyclo[2.2.2]oct-1-yl)-1-propyl-3,7-dihydro-purine-2,6-dione

[0191] (MH⁺=507.30)

Example 13j4-{3-[2-(4-Methoxy-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylicacid

[0192] (MH⁺=481.2)

Example 13k3-Methyl-8-(4-pentyl-bicyclo[2.2.2]oct-1-yl)-1-propyl-3,7-dihydro-purine-2,6-dione

[0193] (MH⁺=387.21)

Example 13l4-[3-(4-Methoxy-phenyl)-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.2.2]octane-1-carboxylicacid

[0194] (MH⁺=453.4)

Example 13m4-[2,6-Dioxo-1,3-bis-(3,3,3-trifluoro-propyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.2.2]octane-1-carboxylicacid, (MH⁺=496.98) Example 13n4-[2,6-Dioxo-1,3-bis-(3,3,3-trifluoro-propyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester

[0195] (MH⁺=511.3)

Example 13o3-[4-(6-Oxo-1,3-dipropyl-2-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid

[0196] (MH⁺=432.98) from5,6-diamino-1,3-dipropyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one,prepared by a literature procedure (Jacobson, K. A.. Kiriasis, L.;Barone, S.; Bradbury, B. A.; Kammula, U.; Campagne, M.; Secunda, S.;Daly, J. W.; Neumeyer, J. L.; Pfleiderer, W. J. Med. Chem. 1989,32,1873-1879).

Example 13p4-(6-Oxo-1,3-dipropyl-2-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid

[0197] (MH⁺=405.04) from5,6-diamino-1,3-dipropyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one,prepared by a literature procedure (Jacobson, K. A.; Kiriasis, L.;Barone, S.; Bradbury, B. A.; Kammula, U.; Campagne, M.; Secunda, S.;Daly, J. W.; Neumeyer, J. L.; Pfleiderer, W. J. Med. Chem. 1989, 32,1873-1879).

Example 144-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester

[0198]4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane1-carboxylic acid (Example 13) (1.50 g, 3.86 mmol) was combined with 60ml of MeOH, and 10 drops of conc'd H₂SO₄. The reaction solution wasbrought to reflux until consumption of starting material ceased. Sat'dNaHCO₃ was then added until neutral pH and the reaction mixture wasconc'd in vacuo. The residue was taken up in EtOAc and washed with sat'dNaHCO₃, brine, and dried over Na₂SO₄. The EtOAc solution was conc'd invacuo to give 1.51 g (97% yield) of a white solid. (MH⁺=403.13)

Example 158-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0199] 4-(2,6-Dioxo-13-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (Example 14) (1.40 g, 3.48 mmol) was combined withLiBH₄ (0.379 g, 17.4 mmol), MeOH (0.141 ml. 3.48 mmol), and 100 ml ofTHF and the resultant mixture was brought to reflux for 18 h. Aftercooling to rt, 50 ml of 1M HCl were added and the mixture conc'd invacuo. The residue was dissolved in EtOAc and washed with 1M HCl, sat'dNaHCO₃, brine, and dried over Na₂SO₄. The EtOAc solution was conc'd invacuo to give 1.15 g (88% yield) of a white solid. (MH⁺=375.50)

Example 164-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde

[0200] To a solution of 0.092 g (0.246 mmol) of8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 15) in 5 ml of CH₂Cl₂ was added 0.125 g (0.295 mmol)Dess-Martin periodinane. The reaction mixture was stirred at rt untilthe oxidation was complete. The reaction solution was filtered through aplug of basic alumina, washed with sat'd NaHCO₃, brine, and dried overNa₂SO₄. The CH₂Cl₂ solution was conc'd in vacuo to give 0.057 g (62%yield) of an off-white solid.(MH⁺=373.30)

Example 173-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid

[0201] Trimethylphosphono acetate (0.0.161 g, 0.886 mmol) was dissolvedin 12 ml of toluene and cooled to between 0-5° C. KHMDS (0.5 M intoluene) (3.54 ml) was added dropwise while stirring over 5 min. Afteran additional 30 min at 0-5° C., 0.300 g (0.805 mmol) of Example 16:4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehydewas added and the reaction was allowed to warm to rt and was stirred for16 h. The reaction mixture was conc'd in vacuo. Dissolved crude materialin 25 ml of MeOH and 10 ml of water added 0.150 g LiOH and stirred at rtovernight. Conc'd in vacuo and redissolved reaction mixture in 15 ml ofwater. Extracted water layer thrice with 20-ml portions of EtOAc,acidified with conc'd HCl, and collected precipitate by suctionfiltration to give 0.190 g (57% yield) of the (trans)-acrylic acidproduct. (MH⁺=415.08)

Example 183-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid

[0202]3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid (Example 17) (0.050 g) was dissolved in 5 ml of MeOH and combinedwith 0.005 g of 10% Pd/C. The reaction vessel was purged three timeswith N₂ and then placed under a balloon of H₂ gas. After 2 h, thereaction mixture was filtered and conc'd to give 0.037 g (74% yield) ofa white solid. (MH⁺=417.30)

Example 18a3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-2-methyl-propionicacid, was made in an analogous manner

[0203] (MH⁺32 431.36)

Example 19{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-methyl-amino}-aceticacid

[0204] To a stirred mixture of 0.100 g (0.257 mmol) of4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid (Example 13), 0.039 g (0.257 mmol) of sarcosine hydrochloride,0.143 ml (1.03 mmol) of NEt₃, and 2 ml anhydrous acetonitrile was added0.103 g (0.270 mmol) of HATU. The reaction solution was stirred at rtfor 16 h. The reaction mixture was concentrated in vacuo and combinedwith 10 ml EtOAc and 10 ml of 10% citric acid. The aqueous layer wasseparated and washed twice with 10-ml portions of EtOAc. The combinedorganic fractions were washed with 10-ml portions of sat'd NaHCO₃ andbrine and conc'd in vacuo. The resultant solid was dissolved in amixture of 5 ml of MeOH and 5 ml of 1 N NaOH and stirred for 16 h. Thereaction solution was conc'd in vacuo, taken up in 10 ml of water, andwashed twice with 10-ml portions of CH₂Cl₂. The aqueous layer wasacidified with conc'd HCl and the resultant precipitate collected bysuction filtration to give 0.094 g (77% yield) of an off-white solid.(MH⁺=460.18)

[0205] The following compounds were made in an analogous manner:

Example 19a4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid (2-dimethylamino-ethyl)-amide

[0206] (MH⁺=459.17)

Example 19b{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-aceticacid methyl ester

[0207] (MH⁺=460.3)

Example 19c3-{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-propionicacid methyl ester

[0208] (MH⁺=389.3)

Example 19d{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-aceticacid

[0209] (MH⁺=446.06)

Example 19e1-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-piperidine-4-carboxylicacid

[0210]¹H NMR (400 MHz, CDCl₃): δ=0.84 (t, 3H), 0.085 (t, 3H), 1.50-1.68(m, 6H), 1.84-1.92 (m, 14H), 2.44 (m, 1H), 2.86 (m, 2H), 3.78 (t, 2H),3.91 (t, 2H), 4.15 (m, 2H).

Example 19f8-(4-Dimethylaminomethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0211] (MH⁺=402.08)

Example 19g8-{4-[(2-Dimethylamino-ethylamino)-methyl]-bicyclo[2.2.2]oct-1-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0212] (MH⁺=445.24)

Example 19h4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid (2-amino-ethyl)-amide

[0213] (MH⁺=431.06)

Example 208-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0214][4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-carbamicacid methyl ester (Example 13d) (8.3 gm, 20 mmol) was refluxed in 40 mlof conc. HCl for 3 h. The reaction mixture was concentrated in vacuo toa solid residue which was triturated in acetonitrile to afford 5.8 gm(77%) as a white solid (MH⁺=360.02)

Example 212-(R)-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yloxy]-propionicacid

[0215]8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 20) (0.100 g. 0.279 mmol) was combined with 1.5 ml of(R)-methyl lactate and 0.075 ml of isoamyl nitrite. The mixture washeated to 60° C. for 2 h and cooled to rt. The reaction mixture wasconc'd in vacuo and the residue was stirred with 8 ml of a 50% MeOHsolution and 0.050 g LiOH overnight. The reaction mixture was conc'd invacuo, taken up in 8 ml of water, the pH of the solution was adjusted to10 and the mixture extracted twice with 6-ml portions of CH₂Cl₂. Thewater layer was acidified with conc'd HCl and the resultant precipitatecollected by suction filtration to give 0.024 g (20% yield).(MH⁺=433.08)

[0216] The following compounds were made in an analogous manner.

Example 21a2-(S)-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid

[0217] (MH⁺=433.10)

Example 21b

[0218]8-(4-Isopropoxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0219] (MH⁺=403.13)

Example 21c8-(4-Allyloxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2.6-dione

[0220] (MH⁺=401.11)

Example 21d[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-aceticacid

[0221] (MH⁺=419.08)

Example 21e1,3-Dipropyl-8-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-bicyclo[2.2.2]oct-1-yl]-3.7-dihydro-purine-2.6-dione

[0222] (MH⁺=511.00)

Example 21f2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-2-methyl-propionicacid

[0223] (MH⁺=447.17)

Example 21g3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid

[0224] (MH⁺=433.6)

Example 21h3-(R)-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-butyricacid

[0225] (MH⁺=447.34)

Example 21i3-(S)-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-butyricacid

[0226] (MH⁺=447.33)

Example 21j3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-2(S)-methyl-propionicacid

[0227] MH⁺=447.32)

Example 21k3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-2(R)-methyl-propionicacid

[0228] MH⁺=447.33)

Example 21l3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-2,2-dimethyl-propionicacid

[0229] (MH⁺=461.32)

Example 21m

[0230][5-(2,6-Dioxo-1,3-dipropyl-2.3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]non-1-yloxy]-aceticacid

[0231] (MH⁺=433.3)

Example 21n

[0232]3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethoxy]-2,2-dimethyl-propionicacid

[0233]¹H NMR (400 MHz, CDCl₃): δ=0.86 (t, 6H), 1.15 (m, 6H), 1.45 (m,6H), 1.58 (td, 2H), 1.67 (td, 2H), 1.84 (m, 6H), 3.32 (s, 2H), 3.38 (s,2H), 3.90 (t, 2H), 3.98 (t, 2H).

Example 21o 3-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]non-1-yloxy]-propionic acid

[0234] (MH⁺=447.32)

Example 21p2-(R)-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]non-1-yloxy]-propionicacid

[0235] (MH⁺=447.26)

Example 228-(4-Phenoxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0236] To a solution of 60 mg of8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 13a) (0.167 mmol) in CH₂Cl₂ (2 ml) was added 27 μL of pyridineand the reaction mixture cooled to 0° C. To this was added 40 μL oftriflic anhydride (0.24 mmol) in CH₂Cl₂ (1 ml). Maintained at 10° C.overnight. The reaction mixture was diluted with CH₂Cl₂ (5 ml) andwashed with cold 1N HCl, sat'd NaHCO₃ and brine. Dried over sodiumsulfate and concentrated in vacuo to afford a yellow oil. The crudetriflate was dissolved in 1,4-dioxane (3 ml) and 100 mg of phenol (1.08mmol was added followed by heating at 80° C. overnight. The reactionmixture was concentrated down and the residue taken up in ethyl acetate(10 ml) washed with 1N KOH (5 ml), sat'd NaHCO₃ (5 ml), 1N HCl (5 ml)and brine. The organic layer was dried over NaSO₄ and concentrated invacuo to a colorless oil which was purified by column chromatography(SiO₂, 1:1 hexanes/EtOAc) to afford 11 mg of title compound as a whitesolid (MH⁺=437.29). The following compounds were prepared in ananalogous manner after saponification of the methyl ester.

Example 22a[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylsulfanyl]-aceticacid

[0237] (MH⁺=435.35)

Example 22b{[4-(2,6-Dioxo-1.3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-methyl-amino}-aceticacid

[0238] (MH⁺=432.31)

Example 22c[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-sulfonyl]-aceticacid

[0239] (MH⁺=467.31)

Example 23 Methanesulfonic acid4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylester

[0240] To a solution of 50 mg of 8-(4-Hydroxybicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 13a) (0.14 mmol) in CH₂Cl₂ (5 ml) was added 20 μL of Et₃N andthe reaction mixture cooled in an ice bath. To this was added 20 μL ofmethanesulfonyl chloride (0.26 mmol) and the reaction mixture kept at10° C. overnight. The reaction mixture was concentrated in vacuo and theresidue taken up in EtOAc and washed 2× with dilute HCl (5 ml). Theorganic layer was dried over NaSO₄ and conc'd. The residue wastriturated in acetonitrile to afford 36 mg (59%) of pure white solid(MH⁺=439.4).

Example 24 Toluene-4-sulfonic acid4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylester

[0241] To a solution of 100 mg of8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 13a) (0.28 mmol) in CH₂Cl (10 ml) was added 40 μL of Et₃N andthe reaction mixture cooled in an ice bath. To this was added 100 mg ofp-toluenesulfonyl chloride (0.52 mmol) and the reaction kept at 10° C.overnight. The reaction mixture was conc'd in vacuo and the residuetaken up in EtOAc and washed 2× with dilute HCl (10 ml). The organiclayer was dried over NaSO₄ and conc'd. The residue was triturated inacetonitrile to afford 78 mg (54%) of pure white solid (MH⁺=515.10).

Example 25N-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-methanesulfonamide

[0242] To a solution 100 mg of8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-l1.3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 20), (0.28 mmol) in 2 ml of pyridine chilled in an ice/waterbath was added 22 μL of methanesulfonyl chloride (0.28 mmol), 30%completion after 24 h at 10° C. Two more aliquots (22 μL and 50 μL) ofmethanesulfonyl chloride were added to drive the reaction to completion.The reaction mixture was concentrated in vacuo to afford a yellow oilwhich was taken up in EtOAc (10 ml) and washed twice with sat'd NaHCO3(5 ml), once with 0.5N HCl and once with brine. The organic layer wasdried over NaSO₄ and conc'd to an oil. Crystallized from acetonitrile toafford 27 mg (22%) as a white solid (MH⁺=438.08). The followingcompounds were prepared in an analogous manner:

Example 25a3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylsulfamoyl]-benzenesulfonicacid

[0243] (MH⁺=579.95)

Example 25b[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylsulfamoyl]-aceticacid

[0244] (MH⁺=482.27)

Example 25c3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylsulfamoyl]-thiophene-2-carboxylicacid methyl ester

[0245] (MH⁺=564.19)

Example 25d3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylsulfamoyl]-thiophene-2-carboxylicacid

[0246] (MH⁺=550.20)

Example 25eN-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]-methanesulfonamide

[0247] (MH⁺=388.32)

Example 25f3-{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]-sulfamoyl}-thiophene-2-carboxylicacid methyl ester

[0248] (MH⁻=578.3)

Example 25g3-{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]-sulfamoyl}-thiophene-2-carboxylicacid

[0249] (MH⁻=564.24)

Example 25h[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylcarbamoyl]-methanesulfonicacid

[0250] (MH⁺=480.13)

Example 261,3-Dipropyl-8-{4-[(thiophen-2-ylmethyl)-amino]-bicyclo[2.2.2]oct-1-yl}-3,7-dihydro-purine-2,6-dione

[0251] To a solution of 100 mg of8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 20) (0.28 mmol) and 37 mg of thiophene-2-carboxaldehyde (0.33mmol) in CH₂Cl₂ (5ml) was added 5 drops of glacial acetic acid and 100mg of sodium triacetoxyborohydride (0.47 mmol). Complete conversionoccurs over 24 h at rt. The reaction mixture was quenched with 2 ml ofethanol and 2 ml of 2N HCl and then concentrated in vacuo to afford acolorless oil which was purified from anhydrous acetonitrile to afford50.8 mg (40%) as a white solid (MH⁺=456.29). The following compoundswere prepared in an analogous manner:

Example 26a{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]-amino}-aceticacid

[0252] (MH⁺=432.32)

Example 26b8-{4-[(1H-Imidazol-2-ylmethyl)-amino]-bicyclo[2.2.2]oct-1-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0253] (MH⁺=440.09)

Example 26c[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylamino]-aceticacid

[0254] (MH⁺=418.15)

Example 26d8-{4-[(Furan-2-ylmethyl)-amino]-bicyclo[2.2.2]oct-1-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0255] (MH⁺=440.30)

Example 26e1,3-Dipropyl-8-(4-{[(thiophen-2-ylmethyl)-amino]-methyl}-bicyclo[2.2.2]oct-1-yl)-3,7-dihydro-purine-2,6-dione

[0256] (MH⁺=470.31)

Example 26f8-(4-{[(3H-Imidazol-4-ylmethyl)-amino]-methyl}-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0257] (MH⁺=454.35)

Example 26g4-{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylamino]-methyl}-benzoicacid

[0258] (MH⁺=494.34)

Example 26h4-({[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]-amino}-methyl)-benzoicacid

[0259] (MH⁺=508.31)

Example 26i1,3-Dipropyl-8-(4-{[(pyridin-4-ylmethyl)-amino]-methyl}-bicyclo[2.2.2]oct-1-yl)-3,7-dihydro-purine-2,6-dione

[0260] (MH⁺=465.33)

Example 26j8-(4-{[(Furan-2-ylmethyl)-amino]-methyl}-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0261] (MH⁺=454.33)

Example 26k5-{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylamino]-methyl}-furan-2-sulfonicacid

[0262] (MH⁺=520.26)

Example 26l8-(4-Cyclopentylamino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0263] (MH⁺=428.38)

Example 26m8-(4-Cyclopentylaminomethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0264] (MH⁺=442.56)

Example 26n

[0265]8-{4-[(1-Methyl-butylamino)-methyl]-bicyclo[2.2.2]oct-1-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0266] (MH⁺=444.60)

Example 274-[3-(4-Hydroxy-phenyl)-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.2.2]octane-1-carboxylicacid

[0267] To a solution of 10 mg of4-[3-(4-Methoxy-phenyl)-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.2.2]octane-1-carboxylic(Example 131) (0.022 mmol) in CH₂Cl₂ (2 ml) cooled in a dry ice/acetonebath was added 1 ml of 1M boron tribromide (1 mmol) in CH₂Cl₂. Thereaction mixture was allowed to come to rt. and maintained for 2 h.After this time the reaction mixture was cooled in dry ice and quenchedwith MeOH. The crude product was isolated after concentration in vacuoand recrystallized from acetonitrile to afford 10 mg of a white solid(MH⁺=439.09). The following compounds were prepared in a similar manner.

Example 27a4-{3-[2-(4-Hydroxy-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylicacid

[0268] (MH⁺=467.4)

Example 27b4-[3-(2-Hydroxy-ethyl)-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.2.2]octane-1-carboxylicacid

[0269] (MH⁺=391.12)

Example 27c4-[3-(4-Hydroxy-phenyl)-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]-bicyclo[2.22]octane-1-carboxylic acid

[0270] (MH⁻=439.09)

Example 27d: 27d3-(4-{3-[2-(4-Hydroxy-phenyl)-ethyl]-2.6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]oct-1-yl)-propionic acid

[0271] (MH⁺=495.12)

Example 27e8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-3-[2-(4-hydroxy-phenyl)-ethyl]-1-propyl-3,7-dihydro-purine-2,6-dione,(MH⁺=439.14) Example 284-{3-[2-(4-Hydroxy-3-iodo-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylicacid

[0272] To a solution of 50 mg4-{3-[2-(4-Hydroxy-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylicacid (Example 27a) (0.107 mmol) in water (10 ml) containing 1 eq. of 1NNaOH (110 μL) was added at rt a solution of 30 mg of iodine (0.107 mmol)in ethanol (1 ml). The reaction mixture was concentrated in vacuo andthe crude product purified by preparative chromatography to afford 12 mg(20%) of desired product (MH⁺=592.89).

[0273] The following compounds were prepared in a similar manner.

Example 28a4-{3-[2-(4-Hydroxy-3,5-diiodo-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylicacid

[0274] (MH⁺=718.50)

Example 28b3-(4-{3-[2-(4-Hydroxy-3-iodo-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]oct-1-yl)-propionicacid

[0275] (MH⁺=621.08)

Example 294-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid amide

[0276] To a solution of 200 mg of4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid (Example 13) (0.515 mmol) in 5 ml of DMF was added 235 mg of HATU(0.618 mmol) and 0.4 ml of N,N-diisopropylethyl amine. Let stir at rtfor 30 min. Added 2.1 ml of 0.5 M NH₃ in dioxane (1.03 mmol) dropwiseover 5 min. Let stir overnight added 0.5 eq. of 0.5M NH₃ in dioxane (0.5ml). Added EtOAc and 1N NaOH until pH=9 and washed with 10% citric acidsat'd NaHCO₃ and brine. Dried over NaSO₄ and conc'd in vacuo to afford80.9 mg (40%) of pure product (MH⁺=388.34).

Example 308-(4-Aminomethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0277] To a solution of 50 mg of:4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid amide (Example 29) (0.129 mmol) in THF (10 ml) was added dropwiseat rt 0.28 ml of 1M borane-THF complex (0.284 mmol) and slowly broughtto reflux after the addition was complete. Refluxed for 3.5 h thencooled and quenched with 10 ml of methanol and brought to reflux.Concentrated in vacuo and the residue taken up in 1 N HCl and washedtwice with CH₂Cl₂ Adjusted pH˜8 and washed twice with EtOAc, dried overNaSO₄ and conc'd in vacuo to afford 30.2 mg (63%) of amine (MH⁺=374.31).

Example 315-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.]octane-2-carboxylicacid

[0278] Using the procedure described in the references, Kraus, W., etal. Liebigs Ann. Chem. 1981, 10, 1826, and Kraus. W., et al. TetrahedronLett. 1978, 445; Filippini, M. -H. et al. J Org. Chem. 1995, 60, 6872,4-oxo-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (6.17 mmol,1.21 g) was converted to4-methoxymethylene-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester.Flash chromatography, eluting with 10% diethyl ether/hexanes providedpure product (0.96 g, 69%) as a liquid (mixture of E/Z isomers). ¹³C NMR(100 MHz, CDCl₃): 14.31 (q), 19.15 (t), 22.97 (t), 23.61 (t), 23.91 (t),29.97 (t), 31.13(t), 32.04 (t), 32.36 (t), 34.61 (t), 34.85 (d), 35.81(t), 43.18 (t), 43.63 (t), 50.47(s), 50.77 (s), 59.63 (q), 59.69 (t),121.04(s), 121.44(s), 137.18 (d), 138.16 (d), 177.60 (s), 177.63 (s).

[0279] Using the procedure described in Example 50,4-methoxymethylene-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester(3.84 mmol, 0.86 g) was converted to4-formyl-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (0.81 g,100%). TLC(silica, 20% Et₂O/hexanes, 20% PMA/EtOH visualization) R_(f)(title compound)=0.29.

[0280] To an ice-cold solution of4-formyl-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (3.85 mmol,0.81 g) was added slowly Jones reagent (2.7 M, 1.43 mL). The reactionwas stirred at ice temperature 20 min. then quenched by addition ofiPrOH, diluted with H₂O and extracted with Et₂O (3×). The combinedorganic extracts were washed with H₂O (2×), brine (1×), and dried(MgSO₄). Filtration and evaporation provided the viscous oilybicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethyl ester (0.76 g, 87%)as a mixture of axial and equatorial acids. ¹³C NMR (100 MHz, CDCl₃):14.16 (q), 19.86 (t), 21.07 (t), 25.98 (t), 29.20 (t), 31.52 (t), 31.87(t), 32.27 (t). 33.39 (t), 37.80 (d), 38.07 (t), 38.10 (d), 42.06 (t),44.80 (d), 45.78 (d), 49.38 (s), 49.60 (s), 60.31 (t), 60.36 (t), 177.08(s), 180.01 (s).

[0281] At 0° C., a solution of DCC (0.5 M in CH₂Cl₂, 5.5 ml) was addedto a solution of bicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethylester (2.52 mmol, 0.57 g), t-BuOH (7.56 mmol, 0.56 g) and DMAP (2.02mmol, 0.247 g) in CH₂Cl) (15 ml). After stirring overnight at RT, thereaction was filtered to remove solids and the filtrate was washed with5% citric acid, saturated NaHCO₃, and dried (MgSO₄). Filtration andevaporation yielded product (0.71 g, 100%) as an oil. MS (ES⁺) 225.24(M+H−tBu).

[0282] A solution of bicyclo [3.2.1]octane-1,4-dicarboxylic acid4-tert-butyl ester 1-ethyl ester (2.52 mmol, 0.71 g) in THF (12 ml) wastreated with IN LiOH (12.6 ml) and stirred at room temperature 3 d. Thereaction was concentrated to remove THF and the aqueous residueextracted with Et₂O to remove neutral impurities. The aqueous phase wasacidified (pH 2-3) at 0° C. with 1N HCl and then promptly extracted withEtOAc. The combined organics were washed with H₂O, brine, and dried(MgSO₄). Filtration and evaporation yielded product (0.48 g, 75%).

[0283] Using the procedure described in Example 8,bicyclo[3.2.1]octane-1,4-dicarboxylic acid 4-tert-butyl ester (1.89mmol, 0.48 g) was reacted with5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (1.89mmol, 0.597 g) to give product (0.81 g, 93%). MS (ES⁺): 463.14 (M+H)

[0284] Using the procedure described in Example 8,5-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[3.2.1]octane-2-carboxylicacid tert-butyl ester (1.75 mmol, 0.81 g) was converted to product(0.501 g, 70%).

[0285] A solution of5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]octane-2-carboxylicacid tert-butyl ester (1.13 mmol, 0.501 g) in CH₂Cl₂ (5 ml) was treatedwith TFA (5 ml). After stirring overnight at RT, the reaction wasconcentrated to dryness. Reverse phase HPLC to provide separation of theequatorial (first band, 0.010 g) and axial (second band, 0.010 g) acidisomers. HPLC (10% to 90% MeCN (0.1% TFA)/H2O (0.1% TFA), YMC 120 A/S-5ODS-AM column. 100 mm×4.6 mm. 1.5 ml/min: R_(T.) (equatorial)=6.49 minR_(T.) (axial)=6.75.

Example 323-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]oct-1-yl]-propionicacid

[0286] A suspension of3-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]oct-1-yl]-acrylicacid methyl ester (Example 12) (0.58 mmol, 0.25 g) and 10% Pd/C (50%H₂O, 0.029 mmol, 0.062 g) in MeOH (20 ml) was hydrogenated at 40 psiovernight. The completed reaction was filtered through Celite, rinsingwith MeOH. Evaporation provided the desired product (0.196 g, 79%) as anoil. MS (ES⁺) 431.18 (M+H)

[0287] A solution of3-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]oct-1-yl]-propionicacid methyl ester (0.456 mmol, 0.196 g) in THF (10 ml) was treated with20% NaOH (2 ml) and stirred overnight at RT. The reaction wasconcentrated to remove the THF. The aqueous residue was acidified (pH2-3) with conc. HCl and iPrOH was added to homogeneity. The solution wasconcentrated on the rotovap until solids just began to separate. Afterchilling in ice I h, the precipitated solids were collected by vacuumfiltration, rinsed with a little H₂O and chased with Et₂O. The solidswere dried on the filter to provide the desired product (0.061 g, 32%).¹³C NMR (100 MHz, CDCl₃): 11.11 (q), 11.26 (q), 20.04 (t), 21.25 (t),21.31 (t), 29.51 (s), 33.97 (t), 35.15 (s), 36.16 (t), 36.39 (t), 43.32(t), 43.41 (t), 45.38 (t), 49.18 (t), 106.01 (s), 149.40 (s), 150.90(s), 156.30 (s), 161.56 (s), 178.54 (s).

Example 33(1RS,2R,5SR)-{[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carbonyl]-amino}-phenylaceticacid

[0288] Using the procedure described in Example 8,5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylic acid (Example 8) (0.052 mmol, 0.020 g) and(R)-phenylglycine methyl ester hydrochloride (0.064 mmol, 0.013 g) werereacted to produce the title compound (0.0134 g, 48%) as a mixture ofdiastereomers. MS (ES⁺) 536.36 (M+H)

[0289] A solution of(1RS,2R,5SR)-{[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]octane-1-carbonyl]-amino}-phenyl-aceticacid methyl ester (0.022 mmol, 0.012 g) in THF (2 ml) was treated with1N LiOH (0.22 ml) for 3 d. The THF was removed on the rotovap, theaqueous residue acidified (pH 2) with 1N HCl and extracted with EtOAc.The combined organics were washed with H₂O, brine and dried (MgSO₄).Filtration and evaporation followed by reverse phase HPLC purificationprovide the desired product (0.0055 g, 48%) as a mixture ofdiastereomers. HPLC (10% to 90% MeCN (0.1% TFA)/H₂O (0.1% TFA), YMC 120A/S-5 ODS-AM column, 100 mm×4.6 mm, 1.5 ml/min: R_(T.)=6.88 min.

[0290] The following compound was prepared in an analogous manner:

Example 33a(1RS,2S,5SR)-{[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carbonyl]-amino}-phenylacetic acid Example 348-(4-Hydroxy-bicyclo[3.2.1]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0291] Using the method described in Example8,4-hydroxy-bicyclo[3.2.1]octane-1-carboxylic acid (Kraus, W., et al.Liebigs Ann. Chem., 1981. 10.1826) (0.50 mmol, 0.085 g) was reacted with5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (0.50mmol, 0.132 g) to provide the desired product (0.081 g, 44%).

[0292] Using the method described in Example 8,4-hydroxy-bicyclo[3.2.1]octane-1-carboxylic acid(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide(0.21 mmol, 0.081 g) was converted to the desired product. MS (ES⁺)361.36 (M+H).

Example 353-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-1-yl]-propionicacid

[0293] Vinylmagnesium bromide (1.0 M in THF. 100 ml) was cooled to 0° C.and the ditosylate derivative of 4,4-bis-hydroxy concentrated underreduced pressure. Purification by chromatography (1:1 hex/EtOAc)afforded 5.0 g of the intermediate alcohol.

[0294] This material (5.0 g) was dissolved in 200 ml of anhydrous DMEand 730 mg of NaH (3 eq) was added. The reaction mixture was stirredunder reflux for 18 h. It was then cooled to rt and quenched with sat aqNH₄Cl and extracted with EtOAc. The organic layer was dried (Na₄SO₄) andconcentrated to afford 3.30 g of the monotosylate intermediate.

[0295] This monotosylate (4.40 g, 13.7 mmol) was dissolved in 20 ml ofDMSO and NaOAc.3 H₂O (18.0 g, 10 eq) was added. The reaction mixture wasstirred at 60° C. for 2 days. It was then diluted with H₂O and extractedwith EtOAc. The organic layer was washed with H₂O, dried (Na₂SO₄) andconcentrated to afford 2.60 g of the acetate derivative, acetic acid1-vinyl-2-oxa-bicyclo[2.2.2]oct-4-ylmethyl ester.

[0296] This acetate (2.60 g, 12.4 mmol) was dissolved in 40 ml of MeOHand K₂CO₃ (8.5 g, 5 eq) was added as a solution in 50 ml of H₂O. Thereaction mixture was stirred at rt for 3 h. It was then concentrated andextracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated. Purification by chromatography (2:1 EtOAc/hex) afforded1.20 g of the alcohol derivative,(1-vinyl-2-oxa-bicyclo[2.2.2]oct-4-yl)-methanol.

[0297] This material (1.20 g, 7.14 mmol) was dissolved in 20 ml ofacetone and cooled to 10° C. CrO₃ (2.1 g. 3 eq) was added as a solutionin 10 ml of 1.5 N H₂SO₄ (aq). The reaction mixture was stirred at 10° C.for 15 min and warmed to rt and stirred for 45 min. It was then dilutedwith H₂O and extracted with EtOAc. The combined organic layers werewashed with H₂O and then extracted with dilute aq KOH. The aqueous layerwas acidified to pH 1 with conc HCl and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄) and concentrated to afford 920 mg ofthe carboxylic acid derivative,1-vinyl-2-oxa-bicyclo[2.2.2]octane-4-carboxylic acid.

[0298] This material was treated with5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione in the same manner asbefore to obtain the corresponding xanthine derivative,1,3-dipropyl-8-(1-vinyl-2-oxa-bicyclo[2.2.2]oct-4-yl)-3,7-dihydro-purine-2,6-dione.

[0299]1,3-Dipropyl-8-(1-vinyl-2-oxa-bicyclo[2.2.2]oct-4-yl)-3,7-dihydro-purine-2,6-dione(400 mg, 1.08 mmol) was suspended in 8 ml of dioxane and 1 ml of a 2.5%solution of OSO₄ in t-BuOH was added, followed by 3 ml of H₂O. After 10min, NaIO₄ was added and the reaction mixture was stirred at rt for 3 h.It was then diluted with H₂O and extracted with EtOAc. The organic layerwas dried (Na₂SO₄) and concentrated to afford the aldehyde intermediate,4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]octane-1-carbaldehyde.

[0300] This material was dissolved in 8 ml of THF and methyl(triphenylphosphoranyline)acetate (720 mg, 2 eq) was added. The reactionmixture was stirred at rt for 18 h. LiOH (155 mg, 6 eq) was added as asolution in 8 ml of H₂O and the resulting reaction mixture was stirredat rt for 4 h. The reaction was then extracted with EtOAc. The organiclayer was dried (Na₂SO₄) and concentrated to afford 250 mg of theacrylate derivative,3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-1-yl]-acrylicacid.

[0301] This material was dissolved in 25 ml of 95% THF and 5% H₂O. 10%Pd/C (80 mg) was added and the reaction mixture was hydrogenated under50 psi of H₂ for 3 h. The reaction mixture was filtered through a pad ofCelite and the filtrate was concentrated. Purification by preparativeHPLC using aq CH₃CN afforded the titled compound. MS (ES⁺) 419.

Example 363-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid 4-aminomethyl-benzylamide

[0302] Step 1: Wang resin (10 g, from Advanced ChemTech, substitution0.7 mmols/g) in 100 ml of dry THF was added CDI (10 g) and the resin wasshaken overnight. Next day the resin was filtered and washed with THF(3×100 ml) and dried.

[0303] Step 2: Resin (2.5 g each, 1.75 mmol) from step 1 was treatedwith eight different diamines (8.75 mmol, 5 eq) in THF (25 ml). For thisexample, 4-Aminomethyl-benzylamine was used. After shaking overnight theresin was washed with THF (3×25 ml), MeOH (3×25 ml). CH₂Cl₂ (3×25 ml)MeOH (3×25 ml) and dried.

[0304] Step 3: Adamantane-1,3-dicarboxylic acid (3.5 g) was taken in DMF(20 ml) DIC (1.36 ml) was added and stirred for 1 hr. The resultinganhydride was added to the resin from step 2. The resin was shakenovernight. Next day the resin was filtered, washed with DMF (3×25 ml),CH₂Cl₂ (3×25 ml) MeOH (3×25 ml) and dried.

[0305] Step 4: 1,3 dipropyl-5,6-diaminouracil.HCl was coupled to theresin from step 3 using PyBOP, N-methyl morpholine in DMF overnight. Theresin was washed with DMF (3×25 ml), CH₂Cl₂ (3×25 ml) MeOH (3×25 ml) anddried.

[0306] Step 5: To the resin from step 4 was added 2 ml of KOH solution(7.5 g of KOH in 200 ml of water: MeOH: THF 10:90:100, 10 eq) and heatedat 60° C. overnight. Next day, after cooling to rt, he resin was washedwith MeOH (3×2 ml), THF (3×2 ml), CH₂Cl₂ (3×2 ml) and dried. The resinwas cleaved using 1:1 TFA: CH₂Cl₂ (2 ml) for 1 hr. The resin wasfiltered and washed with CH₂Cl₂. Combined solvent was removed by SpeedVac. The residue was dissolved in CH₃CN:water 1:1 (2 ml) andlyophilized. Products were characterized by LCMS. Mass (ES⁺ 533).

Example 373-(2.6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid 3-aminomethyl-benzylamide

[0307] Followed the procedure from Example 36. 3-Aminomethyl-benzylaminewas used in step 2. Mass ((ES⁺ 533).

Example 383-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid (3-amino-propyl)-amide

[0308] Followed the procedure from Example 36. 1,3-Diaminopropane wasused in step 2. Mass ((ES⁺ 471).

Example 393-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid {3-[4-(3-amino-propyl)-piperazin-1-yl]-propyl}-amide

[0309] Followed the procedure from Example 36.3-[4-(3-Amino-propyl)-piperazin-1-yl]-propylamine was used in step 2.Mass ((ES⁺ 599).

Example 403-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid [4-(4-amino-cyclohexylmethyl)-cyclohexyl]-amide

[0310] Followed the procedure from Example 36.4,4′-Methylenebis(cyclohexylamine) was used in step 2. Mass ((ES⁺ 607).

Example 413-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid (4-amino-cyclohexyl)-amide

[0311] Followed the procedure from Example 36. Cyclohexane-1,4-diaminewas used in step 2. Mass ((ES⁺ 511).

Example 428-[3-(Piperazine-1-carbonyl)-adamantan-1-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0312] Followed the procedure from Example 36. Piperazine was used instep 2. Mass ((ES⁺ 483).

Example 433-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid amide

[0313] Followed the procedure from Example 36 Step 3. Rink resin wasused instead of wang resin. Mass (ES⁺ 414).

Example 443-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-adamantane-1-carboxylicacid

[0314] Symmetrical anhydride prepared from adamantane 1,3-dicarboxylicacid using DIC in DMF was coupled to 1,3 dipropyl-5,6-diaminouracil.HCl.The product was cyclized using KOH in isopropanol/water. Mass (ES⁺ 415)

Example 458-(3-Hydroxymethyl-adamantan-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0315] Followed the procedure from Example 46. Mass (ES⁺ 401)

Example 465-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carboxylicacid

[0316] Bicyclo[3.3.1]nonane-1,5-dicarboxylic acid monomethyl ester (900mg) was taken in CH₂Cl₂ (25 ml), oxalyl chloride (417 μ) and 2 drops ofDMF were added and stirred at rt for 2 hrs. After two hrs, solvent wasremoved by rotavap. The residue was taken up in 20 ml of CH₂Cl₂. Diaminouracil.HCl (1.25 g), and diisopropylethyl amine(1.7 ml).were added andstirred at rt overnight. Next day, the reaction mixture was diluted withwater, extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was taken in isopropanol:water (2:1, 100ml) and KOH (890 mg) was added and refluxed overnight. Next day aftercooling to rt, solvent was removed by rotavap, diluted with water,acidified with 1N HCl. Precipitate formed was filtered and dried. Yield900 mg. Mass (ES⁺ 403)

Example 478-(5-Hydroxymethyl-bicyclo[3.3.1]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0317]5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carboxylicacid (700 mg) was taken in THF (25 ml). BH₃.THF (1M, 3.5 ml) was addedand stirred at rt overnight. Next day the reaction was quenched withMeOH. Solvent was removed by rotavap. Diluted with water and extractedwith ethyl acetate, washed with water, brine, dried over Na₂SO₄ andconcentrated. Yield 690 mg. Mass (ES⁺ 389)

Example 488-{5-[(2-Dimethylamino-ethylamino)-methyl]-bicyclo[3.3.1]non-1-yl)}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0318] Step 1:8-(5-Hydroxymethyl-bicyclo[3.3.1]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(690 mg) was taken in 50 ml of DMSO. Pyridine.SO₃ (844 mg) andtriethylamine (1.6 ml) were added and stirred overnight. Additionalamount of Pyridine.SO₃ (844) was added and stirred overnight. Thereaction mixture was diluted with ethyl acetate (100 ml) and washed with1N HCl, water, brine, and dried over Na₂SO₄. After concentration, thecrude product was taken to next step without purification.

[0319] Step 2:5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carbaldehyde(40 mg) taken in 5 ml of CH₂Cl₂. N1,N1-Dimethyl-ethane-1,2-diamine (40mg), Na(OAc)₃BH (100 mg), 2 drops of Acetic acid were added and stirredat rt overnight. Next day the reaction mixture was diluted with ethylacetate, washed with sat. NAHCO₃, brine and dried over MgSO₄. Thesolvent was removed under reduced pressure. The crude product waspurified by Preparative HPLC. Mass (ES⁺ 459)

Example 493-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]non-1-yl]-acrylicacid

[0320]5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carbaldehyde(355 mg) was taken in THF (25 ml). Triphenyl-□□-phosphanylidene)-aceticacid methyl ester (614 mg) was added and refluxed overnight. Next dayanother 460 mg of Triphenyl-□□-phosphanylidene)-acetic acid methyl esterwas added and refluxed for 24 hrs. Cooled to RT LiOH (210 mg), water (2ml), MeOH (5 ml) were added and stirred at rt overnight. Solvent wasremoved under reduced pressure. Diluted with water (25 ml), extractedwith ethyl acetate (3×25 ml). Aqueous layer was acidified with 1 N HCland extracted with ethyl acetate (3×50 ml), dried over Na₂SO₄ andconcentrated. Yield 254 mg. Mass (ES⁺ 429).

Example 503-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]non-1-yl]-propionicacid

[0321]3-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]non-1-yl]-acrylicacid (150 mg) was hydrogenated in the presence of 10% Pd/C in THF:MeOH(2:1, 5 ml) @ 60 psi overnight. Catalyst was filtered through celite andthe solvent was concentrated. Solid was purified by crystallizing fromether Yield 105 mg. Mass (ES⁺ 431)

Example 515-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-9-oxa-bicyclo[3.3.1]nonane-2-carboxylicacid

[0322] Step 1:1,3-Dipropyl-7-pyrrolidin-1-ylmethyl-3,7-dihydro-purine-2,6-dione (638mg) was taken in dry THF (10 ml) at −78° C. nBuLi (0.88 ml, 2.5M inhexane) was added slowly. The reaction mixture turned orange and stirredfor 30 min at −78° C. Cyclooct-4-enone (298 mg) was dissolved in 3 ml ofdry THF, added to the reaction mixture. Stirred at −78° C. for 30 min,slowly warmed to rt and stirred for 2 hrs. The reaction mixture wasquenched with sat NH₄Cl and extracted with ethyl acetate (3×50 ml).Combined organic layer was washed with 1N HCl, water, and brine. Driedover anhydrous Na₂SO₄ and concentrated. The crude product was purifiedon silica column, eluted with ethyl acetate:hexane (1:1). Mass (ES⁻ 361)

[0323] Step 2:8-(1-Hydroxy-cyclooct-4-enyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(180 mg, from step 1) was taken in dry MeOH (15 ml) at rt. Carbonmonoxide was bubbled through the solution. PdCl₂ (9 mg) followed byCuCl₂ (201 mg) were added. CO was bubbled for 4 hrs at rt. The reactionmixture turned clear after 3 hrs. After 4 hr MeOH was removed underreduced pressure. Diluted with water, extracted with ethyl acetate.Ethyl acetate layer was washed with water, brine and dried over Na₂SO₄.After concentration, the crude product was purified by silica gelchromatography eluting with ethyl acetate:hexane (1:1). Yield 120 mg.Mass (ES⁺ 419).

[0324] Step 3:5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-9-oxa-bicyclo[3.3.1]nonane-2-carboxylicacid methyl ester (50 mg, from step 2) was taken in MeOH (5 ml). LiOH(15 mg) was added and stirred at rt overnight. Next day MeOH was removedunder reduced pressure, diluted with water and extracted with ethylacetate. Aqueous layer was acidified with 1N HCl, extracted with ethylacetate (3×25 ml). Combined organic layer was washed with brine, anddried over Na₂SO₄. Concentration of the solvent gave a white solid,which was purified by crystallizing from ether. Mass (ES⁺ 405)

Example 528-(5-Hydroxy-9-oxa-bicyclo[3.3.1]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0325] 1,3-Dipropyl-7-pyrrolidin-1-ylmethyl-3,7-dihydro-purine-2,6-dione(638 mg) was taken in dry THF (10 ml) at −78 C. nBuLi (0.88 ml, 2.5M inhexane) was added slowly. The reaction mixture turned orange and stirredfor 30 min at −78° C. Cyclooctane-1,5-dione (280 mg) was dissolved in 3ml of dry THF, added to the reaction mixture. Stirred at −78° C. for 30min, slowly warmed to rt and stirred overnight. The reaction mixture wasquenched with sat NH₄Cl and extracted with ethyl acetate (3×50 ml).Combined organic layer was washed with 1N HCl, water, and brine. Driedover anhydrous Na₂SO₄ and concentrated. The crude product was purifiedon silica column, eluted with ethyl acetate:hexane (1:1). Mass (ES⁺ 377)

Example 535-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-8-oxa-bicyclo[3.2.1]octane-2-carboxylicacid

[0326] Step 1: Followed the same procedure from the example 51 step 1.Cyclohept-4-enone was used instead of Cyclooct-4-enone. Mass (ES⁺ 347)

[0327] Step 2:8-(1-Hydroxy-cyclohept-4-enyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(50 mg) was taken in 10 ml of MeOH at rt. Carbon monoxide was bubbledthrough the MeOH for 10 min. PdCl₂ (25 mg), CuCl₂ (58 mg) were added andCO was bubbled for 3 hrs. Stirred at rt overnight. Diluted with MeOH,water and precipitate formed was filtered through celite. MeOH wasremoved by rotavap, the residue was extracted with ethyl acetate. Ethylacetate layer was washed with water, brine, and dried over Na₂SO₄. Afterconcentration, the crude product was taken in MeOH (5 ml), water (1 ml).LiOH (25 mg) was added and stirred at rt overnight. Next day the MeOHwas removed by rotavap, the residue was taken up in water (20 ml) andextracted with ethyl acetate (2×25 ml). Aqueous layer was acidified with1N HCl, extracted with ethyl acetate (2×50). Ethyl acetate layer waswashed with brine and dried. After concentration the product wasdissolved in ether and filtered through a pad of silica gel.Concentration gave 30 mg of the product. Mass (ES⁺ 391)

Example 54 Phosphoric acidmono-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]ester

[0328]8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione(Example 13a) (180 mg, 0.5 mmol) was dissolved in a mixture of1H-tetrazole (350 mg, 5 mmol) in 10 ml of dry acetonitrile and 10 ml ofdry methylene chloride. At room temperature dibenzyldiethylphosphoramidite (476 mg, 1.5 mmol) was added under nitrogen andthe mixture was stirred for 2 h. Then 70% tert-butyl hydroperoxidesolution (1 ml) was added and the mixture was stirred for 1 h. At 0° C.15 ml of 10% NaHSO₃ was added and the mixture was stirred for another 15minutes. The mixture was then extracted three times with CH₂Cl₂, and theorganic layer was washed water. Evaporation of solvent yieldedPhosphoric acid dibenzyl ester4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylester as a yellow oil, which was purified by column chromatography.Fractions contained Phosphoric acid dibenzyl ester4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl ester was combined and concentrated in vacuum to get 280mg product. MS (M+1) 621.

[0329] Phosphoric acid dibenzyl ester4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylester was dissolved in a mixture of 15 ml methanol and 10 ml of THF,Pd/C (10%, 50 mg) was added to the mixture. Hydrogenation was takenplace at 50 psi for 8 h. Pd/C was filtered off and solvent wasevaporated off. The residue was recrystallized in a mixture of methanoland ethyl acetate to get 190 mg title product (yield 86%). MS (M+1, 441)

Example 55 4-Chloro-2-[(furan-2-ylmethyl)-amino]-5-sulfamoyl-benzoicacid3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionyloxymethylester

[0330] A mixture of3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid (208 mg, 0.5 mmol) , sodium bicarbonate (168 mg, 2 mmol), andtetra-n-butylammonium hydrogensulfate (17 mg, 0.05 mmol) in water (5 ml)and dichloromethane (5 ml) was stirred vigorously at 0° C. After 10 min,to the reaction mixture was added a solution of chloromethylchlorosulfate in dichloromethane (1 ml) and allowed to ambienttemperature and continued to stir vigorously. After a couple of hours,the organic layer was separated and washed with brine. The organicextracts were dried over sodium sulfate. After the solvent was removedin vacuo, the residue was purified by column chromatography on SiO₂using ethyl/hexane (1:5) as an eluent to give (200 mg, yield 86%)3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid chloromethyl ester. MS (M+1 465)

[0331] To a solution of4-Chloro-2-[(furan-2-ylmethyl)-amino]-5-sulfamoyl-benzoic acid (142.5mg, 0.43 mmol) in DMF (3 ml) was added triethyl amine (10 mg, 0.95mmol), and the mixture was stirred for 1 h. The above obtainedchloromethyl ester (200 mg, 0.43 mmol) and NaI (130 mg, 0.86 mmol) wereadded to the reaction mixture. The reaction was let go at roomtemperature overnight. The reaction mixture was concentrated down undervacuo. The residue was participated between Ethyl acetate/water. Theorganic layer was concentrated and was purified under columnchromatography to obtain the title compound (190 mg, yield 58%) as whitesolid. MS(M+1 759)

Example 561-Carboxy-3-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.22]oct-1-yl]-propionyloxymethoxycarbonyl}-propyl-ammonium;trifluoro-acetate

[0332] Followed the procedure for making Example 54,2-tert-Butoxycarbonylamino-pentanedioic acid 1-tert-butyl ester5-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionyloxymethyl}ester was made by using 2-tert-Butoxycarbonylamino-pentanedioic acid1-tert-butyl ester,3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid chloromethyl ester, triethylamine, and NaI in DMF.

[0333] Deprotecting in CH₂Cl₂/TFA (50/50) at room temperature for 8 h,purified in prep. HPLC to get the title compound as TFA salt. (yield20%). MS (M+1 576)

Example 571-Carboxy-3-(N′-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionyl}-hydrazinocarbonyl)-propyl-ammonium;trifluoro-acetate

[0334] A mixture of3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid (208 mg, 0.5 mmol) (Example 18) (208 mg, 0.5 mmol) in THF (15 ml),was added N-methylmorpholine (56 mg, 0.55 mmol) andisobutylchloroformate (75 mg, 0.55 mmol), and the mixture was stirredfor 1 h. Hydrazinecarboxylic acid tert-butyl ester (100 mg, 0.75 mmol)was added to the reaction mixture. The reaction was let go for 2 h. Thereaction mixture was washed with NaHCO3, NaHSO₄, and brine respectively.THF was got rid of under vacuo, and the residue was purified by columnchromatography, followed by deprotection on (CH₂Cl₂/TFA) to get3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-.1-yl]-propionicacid hydrazide as TFA salt. MS(M+1,431).

[0335] The above obtained TFA salt was basified by triethylamine usingthe same mixed anhydride procedural as above reacting with2-tert-Butoxycarbonylamino-pentanedioic acid 1-tert-butyl ester,followed by column chromatography, deprotection in CH₂Cl₂/TFA, prep.HPLC to get the title compound as TFA salt. MS(M+1 559)

Example 58[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-adamantan-1-yl]-aceticacid

[0336] Followed the same procedure from Example 45 using(3-Methoxycarbonylmethyl-adamantan-1-yl)-acetic acid instead ofBicyclo[3.3.1]nonane-1,5-dicarboxylic acid monomethyl ester. Mass (ES⁺443)

Example 594-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cubane-1-carboxylicacid

[0337] To a solution of4-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-cubane-1-carboxylicacid methyl ester (400 mg, 0.966 mmol) in MeOH (20 ml) was added 4 ml ofa 20% aq. NaOH solution and the resulting turbid mixture was heated atreflux overnight (12 h). The cool reaction mixture was concentrated invacuo, diluted with several small ice chips and acidified by thedropwise addition of concentrated HCl. The resulting white precipitatewas collected, dried, and washed with ether to give a white solid (280mg, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.05 (coincident t, 6H), 1.70 (m,2H), 1.83 (m, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 4.27 (m, 3H), 4.38 (m,3H). MS: 383 (MH⁺).

Example 608-(1-Hydroxymethyl-cuban-4-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0338] To a stirred suspension of4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cubane-1-carboxylicacid (100 mg, 0.261 mmol) and HATU (1.1 eq, 0.288 mmol, 110 mg) in 6 mlof MeCN was added Hunig's base (1.1 eq, 0.288 mmol, 37 mg), neat viasyringe. The resulting heterogeneous mixture was stirred for 3 h andNaBH₄ (2.0 eq, 0.522 mmol, 20 mg) was added in one portion. The mixturewas stirred for an additional 2 h, cooled with the aid of an ice bathand acidified by the dropwise addition of concentrated HCl. Theresulting pale yellow precipitate was collected, dried, and resuspendedin MeCN. After stirring overnight the material was collected and driedto afford an off-white powder (50 mg,52%). MS: 369 (MH⁺).

Example 614-(7-Benzyl-2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid

[0339] To a stirred solution of4-[(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-benzyl-carbamoyl]-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (430 mg, 0.843 mmol) in i-PrOH (20 ml) was added 2 NKOH (4.0 eq, 3.37 mmol, 1.7 ml) and the resulting mixture was heated atreflux for 26 h. The cool reaction mixture was concentrated in vacuo togive a semi-solid residue that was diluted with water and extracted withCHCl₃. The aqueous phase was acidified with concentrated HCl to afford awhite precipitate that was collected and dried (381 mg, 91%). MS: 479(MH⁺).

Example 624-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehydeoxime

[0340] To a stirred solution of4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(1.6 g, 4.3 mmol) in MeOH (30 ml) was added hydroxylamine hydrochloride(1.2 eq, 5.16 mmol, 356 mg) and a solution of NaOAc (trihydrate, 1.5 eq,6.45 mmol, 890 mg) in water (10 ml). The resulting mixture was stirredat rt overnight. The mixture was concentrated in vacuo and the solidresidue was suspended in water (15 ml), collected, washed with water anddried to afford a white powder (1.4 g, 84%). This method was also usedin the preparation of:

Example 62a[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acetaldehydeoxime

[0341] MS: 404 (MH⁺).

Example 633-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylonitrile

[0342] To a stirred suspension of4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(535 mg, 1.44 mmol) and (cyanomethyl)triphenylphosphonium chloride (1.2eq, 1.73 mmol, 582 mg) in THF (30 ml) at 0° C. was added KHMDS (0.5 M intoluene, 2.2 eq, 3.16 mmol, 6.3 ml). The resulting mixture was stirredfor 1.5 h at this temperature then heated at 55° C. for 5 h. The coolreaction mixture was partitioned between EtOAc (10 ml) and a saturatedaqueous NH₄Cl solution (20 ml) and the aqueous phase was extracted withEtOAc (20 ml). The combined organic phases were washed with a saturatedaqueous NaCl solution (2×20 ml), dried (MgSO₄), filtered and evaporatedto give a solid residue that was purified by radial chromatography (2 mmplate) using 5% MeOH in CH₂Cl₂ as eluent to afford 425 mg (75%) of abrittle foam (mixture of cis/trans isomers). MS: 396 (MH⁺).

[0343] This method was employed in the synthesis of:

Example 63a{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-vinyl}-phosphonicacid diethyl ester

[0344] MS: 507 (MH⁺).

Example 643-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propiontrile

[0345] A solution of3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylonitrile(110 mg, 0.278 mmol) in MeOH (20 ml) and CH₂Cl₂.(5 ml) was hydrogenatedusing Pd on carbon (10 mol %) and a ballon of hydrogen affixed to a3-way stopcock/ground glass adapter. After stirring overnight, themixture was degassed, filtered through Celite and concentrated in vacuoto give a brittle foam (100 mg, 90%). ¹H NMR (400 MHz, CDCl₃); δ 0.93(coincident triplets, 6H), 1.53 (m, 6H),1.57 (t, 2H), 1.67 (m, 2H), 1.77(m, 2H), 2.00 (m, 6H), 2.24 (t, 2H), 3.99 (t, 2H), 4.05 (t, 2H), 12.17(s, 1H). The following compounds were prepared in an analogous manner:

Example 64a4-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-butyricacid methyl ester

[0346] MS: 445 (MH⁺);

Example 64b{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-ethyl}-phosphonicacid diethyl ester

[0347] MS: 509 (MH⁺).

Example 654-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonitrile

[0348] To a stirred suspension of4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehydeoxime (400 mg, 1.03 mmol) in CHCl₃ (20 ml), cooled with the aid of anice bath, was added POCl₃ (neat, 1.5 eq, 237 mg) and the resultingmixture was allowed to reach ambient temperature overnight (17 h). Thereaction mixture was poured into water, the phases were separated andthe organic phase was washed with saturated aqueous solution of NaHCO₃,dried over Na₂SO₄, filtered and concentrated in vacuo to give a white,brittle foam (360 mg, 95%). MS: 370 (MH⁺).

Example 66[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acetaldehyde

[0349] To a stirred suspension of methoxymethyl triphenylphosphoniumchloride (1.1 g, 3.2 mmol) in THF (60 ml) at −78° C. was added asolution of KHMDS (0.5 M in toluene, 10 ml, 5 mmol). The resultingyellow mixture was stirred at this temperature for 1.5 h and a solutionof4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(372 mg, 1.0 mmol) in THF (12 ml) was added over a period of 20 minutes.The mixture was held at −78° C. for 6 h and allowed to reach ambienttemperature overnight (12 h). The reaction mixture was partitionedbetween saturated aqeuous NH₄Cl (100 ml) and EtOAc (100 ml) and theaqueous phase was extracted with EtOAc (50 ml). The combined organicextracts were washed with saturated aqeuous NaCl (100 ml), concentratedin vacuo, redissolved in THF and concentrated to a volume of approx. 20ml. To the solution was added an equal volume of 1 N HCl and the mixturewas stirred overnight. The mixture was diluted with EtOAc (20 ml), theaqueous phase was separated and extracted with EtOAc (10 ml). Thecombined organic phases were then washed with saturated aqeuous NaCl(2×25 ml), dried (MgSO₄), filtered and concentrated in vacuo. Theresulting orange oil was purified in batches by radial chromatography (2mm plate) using 3% MeOH and 3% THF in CH₂Cl₂ as eluent.Product-containing fractions were combined and concentrated to afford290 mg (75%) of a white solid. MS: 387 (MH⁺).

Example 67[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl-aceticacid

[0350] To a solution of[4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acetaldehyde(170 mg, 0.440 mmol) in t-BuOH (10 ml) and 2-methyl-2-butene (10 eq, 4.4mmol, 470 μL), cooled with the aid of an ice bath, was added NaClO₂ (1.5eq, 0.66 mmol). The resulting yellow solution was allowed to reachambient temperature over a period of 14 h then concentrated in vacuo.The resulting oily residue was partitioned between water (10 ml) andCH₂Cl, (10 ml). The aqueous phase was acidified by the dropwise additionof concentrated HCl and the resulting precipitate was collected, washedwith water and dried to afford 105 mg (59%) as a white powder. ¹H NMR(400 MHz, CDCl₃); d 0.91 (t, 3H), 0.93 (t, 3H), 1.63 (m, 2H), 1.77 (m,2H, partially-obscured), 1.82 (m, 6H), 2.01 (m, 6H), 2.32 (s, 2H), 3.95(m, 2H), 4.07 (m, 2H), 12.74 (s, 1H).

Example 68{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo(2.2.2]oct-1-yl]-ethyl}-phosphonicacid monoethyl ester

[0351] Dissolved{2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-ethyl}-phosphonicacid diethyl ester (30 mg, 59 μmol) in 1 N NaOH (4 ml) and heated thesolution at 80° C. for 3 h. The mixture was allowed to cool to rt andslowly acidified with concentrated HCl. The resulting precipitate wascollected and dried (22 mg, 79%). ¹H NMR (400 MHz, CDCl₃); δ 0.93(coincident triplets, 6H), 1.31 (t, 3H), 1.48 (m, 8H), 1.70 (br m, 6H),1.95 (m, 6H), 3.95 (t, 2H), 4.07 (t, 2H), 12.2 (br s, 1H).

Example 698-[4-(3-Hydroxy-propyl)-bicyclo[2.2.2]oct-1-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione

[0352] To a solution of3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionicacid (417 mg, 1.0 mmol) in THF (25 ml), cooled to 0° C. with the aid ofan ice bath, was added BH; (1.0 M in THF, 3.0 mmol). The resultingmixture was allowed to reach ambient temperature and stirred for aperiod of 60 h. Following the addition of MeOH (10 ml), the mixture wasconcentrated in vacuo to afford a white solid that was dissolved in MeOH(20 ml), stirred at rt for 2 h and evaporated to dryness in vacuo. Theresulting white solid was recrystallized from EtOAc to afford 345 mg(86%) of a white powder. MS: 403 (MH⁻).

[0353] This method was also used to prepare:

Example 69a8-[4-(2-Hydroxy-ethyl)-bicyclo[2.2.2]oct-1-yl]-1,3-dipropyl-3,9-dihydro-purine-2,6-dione

[0354] MS: 389 (MH⁺).

Example 703-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl-propionamide

[0355] To a solution of3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionicacid (510 mg, 1.22 mmol) and HATU (1.1 eq, 1.34 mmol, 511 mg) in DMF (10ml) was added Hunig's base (1.3 eq, 1.60 mmol, 205 mg). After theresulting suspension had been stirred for 1 h, excess ammonia (0.5 M indioxane, 4.0 ml) was added and the mixture was stirred overnight (14 h).The solvent was removed ill vacuo and the resulting residue waspartitioned between CH₂Cl₂ (10 ml) and 1 N HCl (10 ml) with the aid of 2ml MeOH to assist in the transfer and improve solubility. The aqueousphase was extracted with CH₂Cl₂ (2×10 ml), the combined organic phaseswere washed with 1 N HCl (2×10 ml), dried (MgSO₄), filtered andevaporated in vacuo to give an off-white solid (455 mg, 90%). MS: 416(MH⁺).

[0356] This method was employed in the synthesis of the followingcompounds:

Example 70a3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-N-(1H-tetrazol-5-yl)-propionamide

[0357] MS: 484 (MH⁺);

Example 70bN-(2-Cyano-ethyl)-3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionamide

[0358] MS: 469 (MH⁺);

Example 70c2-{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]octane-1-carbonyl]-amino}-3-hydroxy-butyricacid methyl ester

[0359] MS: 504 (MH⁺);

Example 70d 2-55[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]octane-1-carbonyl]-amino}-3-hydroxy-propionicacid methyl ester

[0360] MS: 480 (MH⁺).

Example 71{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-ethyl}-phosphonicacid

[0361] To a solution of{2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-ethyl}-phosphonicacid diethyl ester (30 mg, 59 μmol) in CH₂Cl₂ (8 ml) was added TMSBr(excess) and the resulting mixture was stirred at rt overnight.Additional TMSBr was added and the reaction was heated at 55° C. for 6h. The solvent was removed in vacuo to give an orange solid whose colorwas discharged upon trituration with water. The material was collected,washed with water and dried (20 mg, 77%). MS: 453 (MH⁺).

Example 723-(5-{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-ethyl}-tetrazol-1-yl)-propionitrile

[0362] A solution ofN-(2-cyano-ethyl)-3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionamide(500 mg, 1.06 mmol, 1.0 eq), Ph₃P (2.0 eq, 2.13 mmol, 560 mg), TMSN₃(2.0 eq, 2.13 mmol, 245 mg), and DEAD (2.0 eq, 2.13 mmol, 371 mg) in THF(10 ml) was stirred at rt for 24 h. The reaction vessel was re-chargedwith the reagent cocktail (2.0 eq, 2.13 mmol) and stirring was continuedfor an additional 24 h. The reaction was quenched by the addition of a5% aqueous solution of (NE₄)₂Ce(NO₃)₆ and extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered and evaporated in vacuo to afford a viscous orange oil. Aportion of the material was purified by preparative LC to afford 20 mgof pure material. MS: 494 (MH⁺).

Example 731,3-Dipropyl-8-{4-[2-(1H-tetrazol-5-yl)-ethyl]-bicyclo[2.2.2]oct-1-yl}-3,7-dihydro-purine-2,6-dione

[0363] To a solution of3-(5-{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-ethyl}-tetrazol-1-yl)-propionitrile(150 mg, 0.30 mmol) in THF (20 ml) was added 3 ml of 1N NaOH. Theresulting mixture was stirred at rt for 8 h, concentrated in vacuo andextracted with CH₂Cl₂ (2×10 ml). The aqueous phase was acidified by thecareful addition of concentrated HCl and the resulting precipitate wascollected, washed with water and dried to afford 55 mg (41%) of a whitepowder. MS: 441 (MH⁻).

[0364] This method was also employed in the synthesis of:

Example 73a1,3-Dipropyl-8-[4-(1H-tetrazol-5-yl)-bicyclo[2.2.2]oct-1-yl]-3,7-dihydro-purine-2,6-dione

[0365] MS: 413 (MH⁺).

Example 744-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-butyricacid

[0366] A solution of4-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-butyricacid methyl ester (45 mg, 100 μmol) in THF (4 ml) was treated with 1 MLiOH (2 ml) and the resulting turbid solution was stirred at rtovernight. The solution was concentrated in vacuo diluted with water (2ml) and acidified by the dropwise addition of concentrated HCl. Theresulting precipitate was collected, washed with water and dried toafford a white powder (35 mg, 81 %). MS: 431 (MH⁺).

[0367] This method was employed in the synthesis of the followingcompounds:

Example 74a3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cuban-1-yl]-acrylicacid

[0368] MS: 409 (MH⁺);

Example 74b3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-4,5-dihydro-isoxazole-5-carboxylicacid

[0369] MS: 458 (MH⁺);

Example 74c3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-isoxazole-5-carboxylicacid

[0370] MS: 456 (MH⁺);

Example 74d 2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-thiazole-4-carboxylicacid

[0371] ms: 472 (MH+);

Example 74e2-{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bi-cyclo[2.2.2]oct-1-yl]-ethyl}-thiazole-4-carboxylicacid

[0372] MS: 500 (MH⁺);

Example 74f4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-but-2-enoicacid

[0373] MS: 429 (MH⁺);

Example 74g3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-ylmethyl]-isoxazole-5-carboxylicacid

[0374] MS: 470 (MH⁺);

Example 758-[4-(5-Hydroxymethyl-isoxazol-3-yl)-bicyclo[2.2.2]oct-1-yl]-1,3-dipropyl-3,9-dihydro-purine-2,6-dione

[0375] A solution of4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]octane-1-carbaldehydeoxime (87 mg, 0.22 mmol) and N-chloro succinimide (1.2 eq, 0.27 mmol, 36mg) in DMF (6 ml) was heated in an oil bath at 60° C. for 1.5 h. Thereaction flask was removed from the bath and allowed to cool to rt andpropargyl alcohol (2.0 eq, 0.44 mmol, 25 mg) was added. The flask wasreturned to the oil bath, Et₃N (2.0 eq, 0.44 mmol, 44 mg) was added overa period of 15 minutes and the resulting mixture was heated at 60° C.for 3.5 h. The cool reaction mixture was evaporated in vacuo to afford asolid residue that was purified by radial chromatography (2 mm plate)using a gradient of 2-10% MeOH in CH₂Cl₂ as eluent. Product-containingfractions were combined and concentrated to afford 31 mg (26%) of awhite solid. MS: 442 (MH⁺).

[0376] The following compounds were prepared in an analogous manner:

Example 75a 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-4,5-dihydro-isoxazole-5-carboxylicacid methyl ester

[0377] MS: 472 (MH⁺);

Example 75b3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-isoxazole-5-carboxylicacid methyl ester

[0378] MS: 470 (MH⁺);

Example 75c8-{4-[5-(4-Methoxy-phenyl)-isoxazol-3-yl]-bicyclo[2.2.2]oct-1-yl}-1,3-dipropyl-3,9-dihydro-purine-2,6-dione

[0379] MS: 518 (MH⁺);

Example 75d3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-ylmethyl]-isoxazole-5-carboxylicacid methyl ester

[0380] MS: 484 (MH⁺).

Example 763-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-thiopropionamide

[0381] A suspension of P₄S₁₀ (23 mg, 53 μmol) and Na₂CO₃ (4 mg, 53 μmol)in THF (4 ml) 30 was stirred vigorously for 20 min and3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionamide(20 mg, 45 μmol) was added. The resulting pale yellow solution wasstirred at rt for 1 h, evaporated to dryness and dried in vacuoovernight. The crude material was purified by radial chromatography (1mm plate) using 2-5% MeOH in CH₂Cl₂ as eluent to afford a white solid(11 mg, 55%). MS: 432 (MH⁺).

[0382] This method was employed in the synthesis of the followingcompound:

Example 76a4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]octane-1-carbothioicacid amide

[0383] MS: 404 (MH⁺).

Example 771,3-Dipropyl-8-(4-vinyl-bicyclo[2.2.2]oct-1-yl)-3,9-dihydro-purine-2,6-dione

[0384] To a stirred suspension of methyl triphenylphosphonium chloride(1.07 g, 3.0 mmol) in THF (20 ml) at 0° C. was added n-BuLi (1.4 M inhexane, 2.14 ml, 3.0 mmol). The resulting reddish-brown mixture wasstirred at this temperature for 0.5 h and then at rt for 0.5 h. Asolution of4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(372 mg, 1.0 mmol) in THF (10 ml) was added over a period of 20 minutesand the resulting mixture was stirred overnight (12 h). The reactionmixture was partitioned between saturated aqeuous NH₄Cl (20 ml) andEtOAc (20 ml) and the aqueous phase was extracted with EtOAc (20 ml).The combined organic extracts were washed with saturated aqeuous NaCl(50 ml), dried (MgSO₄), filtered and evaporated in vacuo to afford anoil that was purified by radial chromatography (2 mm plate) using agradient of 0-5% MeOH in CH₂Cl₂ as eluent. Product-containing fractionswere combined and concentrated to afford 140 mg (38%) of a white solid.MS: 371 (MH⁺).

Example 782-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-thiazole-4-carboxylicacid ethyl ester

[0385] A suspension of4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbothioicacid amide (20 mg, 50 μmol) and KHCO₃ (8.0 eq, 400 μmol) in THF (5 ml)was stirred vigorously for 5 min and ethyl bromopyruvate (29 mg, 150μmol) was added neat via syringe. The resulting pale yellow solution wasstirred at rt for 1 h, cooled to 0° C. with the aid of an ice bath andtreated sequentially with pyridine (8.0 eq, 400 μmol) and (F₃CCO)₂O (4.0eq, 42 mg, 200 μmol). The resulting deep red solution was allowed toreach ambient temperature overnight. Following the addition of water (4ml), the mixture was concentrated in vacuo and extracted with CH₂Cl₂(2×10 ml). The combined organic phases were washed with 2 N HCl, dried(Na₂SO₄), filtered and concentrated in vacuo. The solution was purifiedby radial chromatography (I mm plate) using 2-5% MeOH in CH₂Cl₂ aseluent to afford a white solid (22 mg, 88%). MS: 500 (MH⁺).

Example79 cis/trans-1-(2-Chloroethyl)-cyclohexane-1,4-dicarboxylic aciddimethyl ester (II)

[0386] A mixture of n-butyllithium (1.6 M in hexane, 0.275 mol) is addedover 25 minutes to a stirred mixture of diisopropylamine (0.3 mul, 42ml) in dry THF (200 ml) cooled to −78° C. under nitrogen. The resultingmixture is stirred at −78° C. for 30 min. To the mixture is added TMU(1.675 mol, 200 ml) over 20 min. To this mixture of LDA and TMU is added1,4-dimethyl-cyclohexanedicarboxylate (I, 0.25 mol, 45 ml) over 10 min.After stirring an additional 40 min, bromochloroethane (0.30 mol, 25 ml)is added over 10 min. The resulting mixture is stirred at −78° C. for 30min, the cold bath is then withdrawn and the reaction is stirredovernight with warming to 20-25° C. Hydrochloric acid (3N, 200 ml) isthen added and briskly stirred for 10 min. The THF is removed underreduced pressure and the resulting aqueous residue is extracted withhexanes (3×200 ml). The combined organic extracts are washed withhydrochloric acid (3N, 2×200 ml), water (1×100 ml), saturated sodiumbicarbonate (2×100 ml) and saline (1×100 ml) and dried over magnesiumsulfate. Suction filtration and concentration under reduced pressuregives the title compound.

Example 80 Bicyclo[2.2.2]octane-1,4-dicarboxylic acid dimethyl ester(III)

[0387] n-Buthyllithium (2.5 M in hexane, 313 mmol) is slowly added to astirred mixture of diisopropylamine (50 ml, 357 mmol) in dry THF (450ml) cooled to −30° C., under nitrogen. The mixture is stirred for 30 minat −30° C. and cooled to −78° C. In a separate flask, a mixture ofcis/trans-1-(2-chloroethyl)-cyclohexane-1,4-dicarboxylic acid dimethylester (II, Example 79, 80 g, 303 mmol) in THF (1100 ml) and HMPA (225ml, 1280 mmol) is prepared under a nitrogen atmosphere and cooled to−78° C. with stirring. The LDA solution is then added through a transferline over 1 hour. The result mixture is stirred at −78° C. for further 1hour and warmed to 20-25° C. during two hours and stirred for another 30min. Then saturated aqueous ammonium chloride is added. The mixture isconcentrated to about 1 l followed by dilution with 500 ml water andextraction with hexane (3×350 ml). The combined hexane extracts arewashed with saline, dried over sodium sulfate, filtered andconcentrated. The crude product is crystallized from hexane to give thetitle compound.

Example 81 Bicyclo-[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester(IV)

[0388] A mixture of Bicyclo[2.2.2]octane-1,4-dicarboxylic acid dimethylester (III, Example 80, 20.4 g, 89.5 mmol), barium hydroxide octahydrate(14 g, 44.7 mmol) in methanol (160 ml) and water (40 ml) is stirred at20-25° C. for 18 hour. The mixture is diluted with water (600 ml) andextracted with hexane (150 ml×2). The aqueous mixture is acidified (6 Nhydrochloric acid) to pH=1-2 and extracted with chloroform (150 ml×2).The combined chloroform extracts are concentrated. The residue isdissolved in toluene, filtered and concentrated to give the titlecompound, mp=169-173° C.

Example 82 4-Chlorocarbonylbicyclo[2.2.2]octane-1-carboxylic acid methylester (V)

[0389] Bicyclo-[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV,Example 81, 1 wt) is dissolved in dichloromethane (6.25 vol) anddimethylformamide (0.025 vol) is added. Concomitantly oxalyl chloride(0.5125 vol) is dissolved in dichloromethane (0.625 vol) and theresulting mixture is added to the mixture containing thebicyclo-[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV) atbetween 12 to 17° C., taking care for gas evolution. The mixture isstirred at 15 to 25° for 2 to 4 hours which is monitored by (TLC;dichloromethane/methanol: 9/1, visualization Bromocresol green). Thesolvent is removed under reduced pressure at 40 to 45°, dichloromethane(5 vol) is added, stirred for 5 to 15 min and removed under reducedpressure at 40 to 45°. The process is repeated by adding dichloromethane(5 vol), stirring for 5 to 15 min and removing under reduced pressure at40 to 45°. Acetonitrile (6.25 vol) is then added to give the titlecompound in solution.

Example 83a4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydropyrimidin-5-ylcarbamoyl)bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (VII)

[0390] Diaminodipropyluracil hydrochloride (VI, 1.36 wt) is suspended inacetonitrile (12.5 vol), cooled to 0 to 5° C. and triethylamine (2.46vol) is added between 0 to 10° C. The mixture is then cooled to 0 to 5°C. A mixture of 4-chlorocarbonylbicyclo[2.2.2]-octane-1-carboxylic acidmethyl ester (V, Example 82) in acetonitile is added to thediaminodipropyluracil mixture between 0 to 20° C. The reaction mixtureis then warmed to 15 to 25° C. and stirred for 15 to 20 hours by whichtime all of the 4-chlorocarbonylbicyclo[2.2.2]octane-1-carboxylic acidmethyl ester (V) is consumed (TLC; dichloromethane/methanol, 9/1;visualization Bromocresol green). The reaction mixture is diluted withwater (3.12 vol) and concentrated under reduced pressure at 40 to 45° C.(18 to 20 vol of solvent is removed). The concentrate is extracted withethyl acetate (3×6 vol) and the combined organics are washedsequentially with citric acid (10%, 3 x 3.12 vol), hydrochloric acid(1M, 2.5 vol), water (3.12 vol), saturated sodium bicarbonate (3.12 vol)and saline (3.12 vol). The mixture is dried over magnesium sulphate(0.75 wt) for 5 to 15 min, filtered, washed with ethyl acetate (1 vol)and the solvent removed under reduced pressure at 40 to 45° C. to givethe title compound.

Example 83b4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (VII, Step E)

[0391] 4-Chlorocarbonylbicyclo[2.2.2]octane-1-carboxylic acid methylester (V, Example 82, 0.562 kg) is dissolved in dichloromethane (3.55 l)and dimethylformamide (0.014 l) is added. Concomitantly oxalyl chloride(0.291 l) is dissolved in dichloromethane (0.355 l) and the resultingmixture is added to the4-chlorocarbonylbicyclo[2.2.2]octane-1-carboxylic acid methyl ester (V,Example 82) mixture at between 12 to 17° C. The mixture is stirred at 15to 25° C. for 2 hours, by which time all of the4-chlorocarbonylbicyclo[2.2.2]octane-1-carboxylic acid methyl ester (V,Example 82) is consumed (TLC; dichloromethane/methanol, 9/1;visualization with Bromocresol green). The solvent is removed underreduced pressure at 40 to 45°, dichloromethane (0.355 l) is added,stirred for 5 to 15 min and removed under reduced pressure at 40 to 45°C. The process is repeated by adding dichloromethane (2.83 l), stirringfor 5 to 15 min and concentrating in vacuo at 40 to 45° C. Acetonitrile(3.54 l) is then added (mixture A). In a separate flask,diaminodipropyluracil hydrochloride (VI, 0.772 kg) is suspended inacetonitrile (7.09 l), cooled to 0 to 5° C. and triethylamine (1.40 l)is added between 0 to 10° C. (mixture B). The mixture is then cooled to0 to 5° C. Mixture A is added to mixture B between 0 to 20° C. Thereaction mixture is warmed to 15 to 25° C. and stirred for 16 hours bywhich time all of the acid chloride is consumed (TLC;dichloromethane/methanol, 9/1; visualization with Bromocresol green).The reaction mixture is diluted with water (1.77 l) and concentratedunder reduced pressure at 40 to 45° C. The concentrate is extracted withethyl acetate (3×3.41 l) and the combined organics are washedsequentially with citric acid (10%, 3×1.77 l), hydrochloric acid (1 M,1.42 l), water (1.77 l), saturated sodium bicarbonate (1.77 l) andsaturated saline (1.77 l). The mixture is dried over magnesium sulfate(0.426 kg) for 5 to 15 min, filtered, washed with ethyl acetate (0.568l) and the solvent evaporated under reduced pressure at 40 to 45° C. togive the title compound.

Example 84a4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetraydro-1H-purin-8-yl)-bicyclo[2.2.21octane-1-carboxylic acid methyl ester (VIII)

[0392] 4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydropyrimidin-5-ylcarbamoyl)bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (VII, Example 83a, 1 wt) and isopropanol (4.76 vol)are mixed and stirred under nitrogen. Potassium hydroxide (2M, 4.76 vol)is added. The title compound is formed but not isolated.

Example 85a4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid (IX)

[0393]4(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetraydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (VIII, Example 84a) in the potassium hydroxideenvironment is heated at reflux for 2 to 3 hr until complete as measuredby NMR. The mixture is then cooled to 10 to 25° C. Water (11.16 vol) isadded followed by toluene (1.25 vol) and the contents are stirredvigorously for 5 to 15 minutes. The layers are separated. Toluene (1.25vol) is added to the aqueous layer and the mixture is stirred vigorouslyfor a 5 to 15 minutes. The layers are separated. Toluene (1.25 vol) isadded to the aqueous layer, stirred vigorously for 5 to 15 minutes andthe layers are separated. The aqueous phase is then cooled to between 0and 10° C. and acidified with concentrated hydrochloric acid (0.74 vol),maintaining the temperature below 10° C. The mixture is stirred atbetween 0 and 10° C. for 60 to 90 minutes. The solid is collected byfiltration and dried under reduced pressure to give the title compound.

Examples 84b and 85b4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid (VIII, IX, Steps F and G)

[0394]4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (VII, Example 83b, 0.760 kg) and isopropanol (3.62 l)are combined. The mixture is stirred under nitrogen and potassiumhydroxide (2 M, 3.62 l) is added. The contents are heated at reflux for3 hr (test for reaction completion by NMR). The mixture is then allowedto cool to 10 to 25° C. Water (8.48 l) is added followed by toluene(0.95 l) and the contents are stirred vigorously for 5 to 15 minutes.The layers are separated. Extraction with toluene (0.95 l) is performedtwo additional times. The aqueous phase is then cooled to between 0 and10° C. and acidified with concentrated hydrochloric acid (0.562 l). Themixture is stirred at between 0 and 10° C. for 60 minutes. Solid productis collected by filtration and dried under reduced pressure at 50 to 60°C. to give the title compound.

Example 86a 8-(4-Hydroxymethylbicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Step H)

[0395]4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid (IX, Example 85a, 1 wt) and tetrahydrofuran (11 vol) are mixedunder nitrogen. Borane.tetrahydrofuran complex (1 M) in THF (5.1 vol) isadded at such a rate as to maintain the internal temperature between 10to 20°. The mixture is stirred at 10 to 20° for 17 to 20 hours until allof the acid (X) is consumed (TLC; dichloromethane/methanol, 9/1,visualization UV then potassium permanganate). Methanol (4.2 vol) isadded to the reaction, prior to heating at reflux for 45 to 75 min. Thereaction is cooled to between 15 and 40° and the solvent removed byreduced pressure at 40 to 45°. The residue is partitioned between ethylacetate (16.6 vol) and hydrochloric acid (1 M, 2.5 vol) and the aqueouslayer is removed with any undissolved solid material. This mixture isclarified and the residual organic phase from the filtration of theaqueous layer/solid mixture is combined with the bulk organic phase.Saturated sodium hydrogen carbonate (2.5 vol) is added and the layersseparated, retaining any solids with the aqueous phase. This aqueousphase/solid mixture is filtered and the residual organic phase fromthese mother liquors is combined with the bulk organic phase. Thecombined organic phases are washed with saline (2.5 vol), the layers areseparated and any residual solid is retained with the aqueous phase. Theaqueous phase/solid mixture is filtered and any organic in the motherliquors from the filtration is combined with the bulk organic phase,dried with magnesium sulphate (0.5 wt) for 5 to 15 mins, filtered,washed with ethyl acetate (I vol) and the solvent removed under reducedpressure at 40 to 45° to give the title compound.

Example 86b 8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Step H)

[0396]4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane1-carboxylic acid, IX, Example 85b, 0.82 kg) and tetrahydrofuran (9.02l) are mixed under nitrogen and borane.tetrahydrofuran complex (1 M) inTHF (4.18 l) is added at such a rate as to maintain the internaltemperature between 10 to 20°. The reaction mixture is stirred at 10 to20° for 17 hours until all of the starting material is consumed (TLC;dichloromethane/methanol, 9/1; visualization UV then potassiumpermanganate). Methanol (3.44 l) is added to the reaction mixture, andthe mixture is heated to reflux for 1 hr. The reaction is cooled tobetween 15 and 40° and the solvent removed by reduced pressure at 40 to45°. The residue is partitioned between ethyl acetate (13.61 l) andhydrochloric acid (1 M, 2.23 l) and the aqueous layer is removed withany undissolved solid material. The mixture is clarified and theresidual organic phase from the filtration of the aqueous layer/solidmixture is combined with the bulk organic layer. Saturated sodiumhydrogen carbonate (2.23 l) is added and the layers separated, retainingany solids with the aqueous phase. The aqueous phase/solid mixture isfiltered and the residual organic phase from these mother liquors arecombined with the bulk organic layer. The combined organic layers arewashed with saturated saline (2.23 l), the layers are separated andresidual solids are retained with the aqueous phase. The aqueouslayer/solid mixture is filtered and organics in the mother liquors fromthe filtration are combined with the bulk organic layer, dried withmagnesium sulfate (0.41 kg), filtered, washed with ethyl acetate (0.82l) and the solvent removed under reduced pressure at 40 to 45° to givethe title compound.

Example 87a4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(XI)

[0397]8-(4-Hydroxymethylbicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione(X, Example 86a, 1 wt) and dimethyl sulphoxide (4 vol) are mixed andstirred under nitrogen; the mixture is stirred for 5 to 15 mins andtriethylamine (2.42 vol) is added. A mixture of sulphur trioxidepyridine complex (1.275 wt) in dimethyl sulphoxide (6 vol) is added,maintaining the internal temperature below 30°. The temperature isadjusted to 14 to 20° and the reaction mixture is then stirred at 14 to20° for 16 to 20 hours until complete by NMR. If there is any startingalcohol remaining sulphur trioxide pyridine complex (0.15 wt) is addedand the reaction stirred for a further 2 to 3 hours at 14 to 20°. Ethylacetate (20 vol) and hydrochloric acid (1 M, 10 vol) are added to thereaction mixture and stirred vigorously for 5 to 15 mins. The phases areseparated and the organic phase is washed with hydrochloric acid (1 M,10 vol). The phases are separated and the organic phase is again washedwith hydrochloric acid (1 M, 10 vol). The phases are separated and theorganic phase is washed with saline (5 vol), dried over magnesiumsulphate (0.5 wt) for 5 to 10 mins and filtered. The filter cake iswashed with ethyl acetate (1 vol). The solvent is removed under reducedpressure at 40 to 45° to give the title compound.

Example 87b4-(2,6Dioxo1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(XI, Step I)

[0398]8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione(X, Example 8, 0.440 kg) and dimethyl sulphoxide (1.76 l) are mixedunder nitrogen, stirred for 5 to 15 mins and triethylamine (1.065 l) isadded. A mixture of sulphur trioxide pyridine complex (0.561 kg) indimethyl sulphoxide (2.64 l) is added, maintaining the internaltemperature below 30° C. The internal temperature is adjusted to 14 to20° C. and the reaction mixture is stirred at 14 to 20° C. for 20 hours.Ethyl acetate (8.80 l) and hydrochloric acid (1 M, 4.40 l) are added tothe reaction and the mixture is stirred vigorously for 15 mins. Thelayers are separated and the organic layer is washed twice more withhydrochloric acid (1 M, 4.40 l). The organic layer is then washed withsaline (2.20 l), dried over magnesium sulfate (0.223 kg) for 10 mins,filtered and the filter cake is washed with ethyl acetate (0.440 l). Thesolvent is evaporated under reduced pressure at 40 to 45° to give thetitle compound.

Example 88cis/trans-3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]acrylicacid methyl ester (XII)

[0399]4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(XI, Example 87a, 1 wt) and tetrahydrofuran (16.5 vol) are mixed undernitrogen and methyl(triphenylphosphoranylidene) acetate (1.85 wt) isadded. The reaction mixture is heated to 65 to 75° C. and the reactionmixture stirred at this temperature until the starting aldehyde has beenconsumed as determined by NMR. The mixture is cooled to 35 to 40° C. anda solution of lithium hydroxide (0.45 wt) in water (16.5 vol) is added.The mixture is heated to reflux and the mixture stirred at reflux untilthe hydrolysis of the ester is complete (as determined by NMR, typicalreaction time 3 to 6 hours). The reaction mixture is cooled to 35 to 40°and the organic solvent removed in vacuo at 40 to 45°. Ethyl acetate (10vol) and water (6 vol) are added to the aqueous residue and the mixtureis vigorously stirred for 5 to 15 mins. The phases are separated and theaqueous phase is washed with ethyl acetate (2×10 vol). The aqueous phaseis filtered. The filtrate is cooled to 0 to 5° and acidified to pH=1with concentrated hydrochloric acid (0.90 vol). The mixture is stirredat 0 to 5° for 45 to 75 mins. The resultant slurry is filtered and thefilter pad washed with water (1 vol). The solid is dried in vacuo at 45to 55° for 16 to 24 hours to give the title compound.

Examples 893-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo12.2.2]oct-1-yl]-acrylic acid (XIII, Steps J and K)

[0400]4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(XI, Example 97b, 0.300 kg) and tetrahydrofuran (4.95 l) are mixed underan atmosphere of nitrogen and methyl(triphenylphosphoranylidene) acetate(0.555 kg) is added. The reaction mixture is heated to 65 to 75° and thereaction mixture stirred at this temperature until the starting aldehydeis consumed (17 hours). The mixture is cooled to 35 to 40° and a mixtureof sodium hydroxide (0.132 kg) in water (4.95 l) is added. The mixtureis heated to reflux and stirred until the hydrolysis of the ester iscomplete (3 hours). The reaction mixture is cooled to 35 to 40° and theorganic solvent removed in vacuo at 40 to 45°. Ethyl acetate (3.00 l)and water (1.80 l) are added to the aqueous residue and the mixture isvigorously stirred for 15 mins. The layers are separated and the aqueouslayer is washed with ethyl acetate (2×3.00 l). The aqueous layer isfiltered, the filtrate is cooled to 0 to 5° and acidified to pH=1 withconcentrated hydrochloric acid (0.270 l). The mixture is stirred at 0 to5° for 1 hour. The resultant slurry is filtered and the filter padwashed with water (0.300 l). The solid is dried in vacuo at 45 to 55°for 24 hours to the title compound.

Example 903-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]propionic acid (XIV)

[0401]3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid, (XIII, Example 89, 1.934 kg), tetrahydrofuran (11.875 l), water(0.625 l) and activated charcoal (0.100 kg) are mixed and stirred at 16to 25° for 30 minutes and then filtered. The filter cake is washed withTHF (0.500 l). A separate flask is charged with palladium on carbon(10%, 0.130 kg) and the filtered tetrahydrofuran/water mixture of thestarting material. The flask is placed under reduced pressure and purgedwith nitrogen. The reduced pressure/nitrogen purge is repeated twice.The flask and contents are placed under reduced pressure and purgedtwice with hydrogen. The mixture is vigorously stirred under anatmosphere of hydrogen at 20° C. for 3 hours. The reaction vessel isevacuated and purged with nitrogen three times. The contents arefiltered through celite (0.500 kg) and the filter cake washed withtetrahydrofuran (2×0.500 l). The solvent is removed under reducedpressure at 40 to 45°. Aqueous acetonitrile (50%, 7.540 l) is added tothe residue and the slurry is aged at 15 to 25°, with stirring, for 3hours. The slurry is cooled to between 0 and 5° and filtered. The filtercake is washed with aqueous acetonitrile (50%, 1.93 l), transferred todrying trays and dried at 50 to 60° under reduced pressure for 24 hoursto give the title compound.

Example 91 4-Hydroxymethylbicyclo[2.2.2]octano-1-carboxylic acid methylester (XVI, Step VI)

[0402] 4-methyl morpholine (15 ml, 136 mmol) and iso-butyl chloroformate(15.0 ml, 123 mmol) are successively added tobicyclo[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV) in DME(165 ml), cooled to −7° C.

[0403] After about 2 minutes, the reaction mixture is filtered and thesolid is rinsed with DME. The combined filtrates are transferred to atwo liter round-bottomed flask and cooled to −5° C. An aqueous solutionof sodium borohydride (7.02 g, 185 mmol), in 75 ml water is added overabout 1 minute (CAUTION: massive evolution of gas). After 10 minutes,the reaction mixture is diluted with water (100 ml) and extracted withethyl acetate (3×250 ml). The combined organic layers are washed withsaline (150 ml×3), dried over anhydrous sodium sulfate and concentratedto give the title compound.

Example 92 4-Hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid (XVII,Step N)

[0404] Lithium hydroxide (2 N, 250 ml) is added to a mixture of4-hydroxymethyl-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester(XVI, Example 91) in a mixture of THF (50 ml) and methanol (75 ml). Theresulting reaction mixture is stirred at 20-25° for 16 hr, and thenconcentrated. The residue is diluted with water (30 ml) and washed withmethylene chloride (100 ml) and ethyl acetate (100 ml). The aqueouslayer is acidified with concentrated hydrochloric acid pH about 0 andextracted with ethyl acetate (3×250 ml). The ethyl acetate layers arecombined and washed with saline (3×50 ml), dried over anhydrous sodiumsulfate and concentrated to give the title compound, NMR (400 MHz,CDCl₃) δ 3.09, 1.72 and 1.29.

Example 93 4-Hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid benzylester (XVIII, Step O)

[0405] 4-Hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid (XVII,Example 14, 24.8 g 135 mmol) is dissolved in DMF (950 ml). Anhydrouspotassium carbonate (25 g, 181 mmol) is added to the solution slowly.Benzyl bromide (22 g, 12.94 mmol) is then added. The reaction mixture isheated at 80° for 16 hr. To the reaction mixture is added water (150 ml)and concentrated to give an oil, which was dissolved in ethylacetate/hexane (5/1, 500 ml). The mixture is washed with saline (2×200ml), dried over anhydrous sodium sulfate and concentrated to give thetitle compound, NMR (400 MHz, CDCl₃) δ 7.39, 5.11, 3.28, 1.84 and 1.41.

Example 94 4-Formylbicyclo[2.2.2]octane-1-carboxylic acid benzyl ester(XIX, Step P)

[0406] Oxalyl chloride (COCl)₂ (16.5 ml, 188 mmol) in methylene chloride(150 ml) is cooled to −63°. DMSO (18 ml, 362 mmol) is then addeddropwise. The resulting mixture is stirred for 30 minutes and then amixture of 4-hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid benzylester (XVIII, Example 93, 34.5 g, 125 mmol) in methylene chloride (100ml) is added over 15 minutes. After another 30 minutes,triethylethylamine (70 ml, 502 mmol) in methylene chloride (30 ml) isadded over 25 minutes. (Extra Caution: extremely exothermic reactionwhen the first equivalent of the triethylamine is added.) The reactionmixture then stirred for another 45 minutes and the cooling bath isremoved and allowed to warm up to 20-25°. Water (50 ml) is added and theorganic layer is separated, dried over anhydrous sodium sulfate andconcentrated to give the title compound, NMR (400 MHz, CDCl₃) δ 9.51,7.32, 5.11, 1.88 and 1.64.

Example 95cis/trans-4-(2-Methoxycarbonylvinyl)bicyclo[2.2.2]octane-1-carboxylicacid benzyl ester (XX, Step Q)

[0407] Methyl (triphenylphosphoranylidene) acetate (60.2 g, 173 mmol) isadded to a stirred solution of 4-formylbicyclo[2.2.2]octane-1-carboxylicacid benzyl ester (XIX, Example 94, 33.5 g, 123.2 mmol) in THF (550 ml).This mixture is then heated to gently reflux for 16 hr. The reactionmixture is cooled to 20-25° and to this is added saturated ammoniumchloride (75 ml) and stirred for 10 minutes. Ethyl acetate (250 ml) andisomeric hexanes (300 ml) are added and stirred for 10 minutes. Theresulting mixture is filtered through a plug of silica gel (850 g) witha thin layer of celite on the top. The solid is washed with ethylacetate/hexane (1/1, 250 ml). The filtrates are combined andconcentrated to give the title compound, NMR (400 MHz, CDCl₃) δ 7.24,6.81, 5.59, 5.01, 3.63, 1.81 and 1.48.

Example 96 4-(2-Methoxycarbonylethyl)bicyclo[2.2.2]octane-1-carboxylicacid (XXI, Step R)

[0408] 4-(2-Methoxycarbony-vinyl)-bicyclo[2.2.2]octane-1-carboxylic acidbenzyl ester (XX, Example 95, 35 g, 106.6 mmol) is dissolved in ethylalcohol/water (9/1, 300 ml) and is placed in a Porter pressure bottle.Palladium on carbon (10%, 5 g) is added and the mixture is hydrogenated(65 psi) for 48 hr. The reaction mixture is filtered through a pad ofcelite and the combined filtrates were concentrated to give the titlecompound, NMR (400 MHz, CDCl₃) δ 3.58, 2.18, 1.74, 1.44 and 1.38.

Example 97 3-(4-Chlorocarbonylbicyclo[2.2.2]oct-1-yl) propionic acidmethyl ester (XXII, Step S)

[0409] Oxalyl chloride (794 mg, 6.25 mmol) in methylene chloride (5 ml)plus a drop of DMF is slowly added to a mixture of4-(2-methoxycarbonyethyl)-bicyclo[2.2.2]octane-1-carboxylic acid (XXI,Example 96,1.2 g, 5 mmol) in methylene chloride (20 ml). The reactionmixture is stirred for 2 hr and concentrated to give the title compound,NMR (400 MHz, CDCl₃) δ 3.66, 2.29, 1.95, 1.54 and 1.46.

Example 983-[4-(6Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetraydropyrimidin-5-ylcarbamoyl)bicyclo[2.2.2]oct-1-yl]propionicacid methyl ester (XXIII, Step T)

[0410] To a suspension of 5,6-diamino-1,3-dipropyl uracil hydrochloride(1.45 g, 5.5 mmol) in methylene chloride (15 ml) is added triethylamine(2.6 ml, 18.7 mmol) slowly at −10° in an ice bath and to this ias addeda mixtue of 3-(4-chlorocarbonyl-bicyclo[2.2.2]oct-1-yl)-propionic acidmethyl ester (XXII, Example 97,1.3 g, 5 mmol) also in methylene chloride(5 ml) over a period of 10 minutes. The reaction is then warmed to20-25° and the stirring is continued for another 16 hrs. Water (2 ml) isadded to the reaction mixture which is then concentrated. Theconcentrate is dissolved in ethyl acetate (20 ml) and is washed withcitric acid (5% citric acid, 2×10 ml), saline (10 ml), dried overanhydrous sodium sulfate and concentrated to give the title compound,NMR (400 MHz, CDCl₃) δ 7.40, 5.46, 3.81, 3.59, 2.21, 1.88, 1.67, 1.62,1.52, 1.46, 0.99 and 0.92.

Example 993-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]oct-1-yl]propionicacid methyl ester (XXIV, Step U)

[0411] See Example 100;3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]oct-1-yl]propionicacid methyl ester (XXIV) is produced in situ and converted to the freeacid in Example 100 as part of a one pot procedure.

Example 1003-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]propionicacid (XIV, Step V)

[0412]3-[4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetraydropyrimidin-5-ylcarbamoyl)bicyclo[2.2.2]oct-1-yl]propionicacid methyl ester (XXIII, Example 98, 1.95 g, 4.35 mmol) is dissolved in2-propanol (15 ml) and potassium hydroxide (2N, 15 ml) is added. Theresulting mixture is heated to slightly refluxing for an hour and thenis cooled to 20-25° C. Water (15 ml) is added and the mixture is washedwith methylene chloride (3×15 ml). The aqueous layer is acidified to pHabout 2 with concentrated hydrochloric acid. The precipitate iscollected by filtration and dried in a vacuum oven for 16 hr to give thetitle compound, HPLC analysis showed the purity was >96%.

Example 101 cis/trans-1-(2-Iodoethyl)-cyclohexane-1,4-dicarboxylic aciddimethyl ester (XXV)

[0413] A mixture ofcis/trans-1-(2-chloroethyl)-cyclohexane-1,4-dicarboxylic acid dimethylester (II Example 79, 8.1 mmol, 2.12 g), sodium iodide (8.88 mmol, 1.33g) and THF (20 ml) are stirred and refluxed 6 hr. The mixture is cooledto 20-25°, diluted with hexanes (50 ml) and washed with water (2×25 ml).The combined aqueous washes are extracted with hexanes (1×25 ml). Thecombined organic extracts are washed with water (25 ml) to which hasbeen added a few drops of saturated Na₂S₂O₄ solution and saline (1×25ml) and dried over magnesium sulfate. Suction filtration andconcentration under reduced pressure gives the title compound, CMR(CDCl₃) δ 1.99, 25.71, 25.80, 33.09, 42.00, 44.03, 46.09, 52.19, 52.7,67.72, 175.25 and 175.64.

Example 102 Bicyclo[2.2.21octane-1,4-dicarboxylic acid dimethyl ester(III)

[0414] To a mixture ofcis/trans-1-(2-iodoethyl)-cyclohexane-1,4-dicarboxylic acid dimethylester (XXV, Example 101, 2.14 g, 6.04 mmol) in THF (20 ml) and TMU (2.9ml, 24.16 mmol) is added at −78° a solution of LDA (from 1.02 mldiisoproylamine and 4.16 ml 1.6 M n-butyllithium) in THF (9 ml). Thereaction is stirred with gradual warning to 20-25°. Hydrochloric acid(3N, 20 ml) is added and briskly stirred 10 min. The THF is removedunder reduced pressure and the resulting aqueous residue is extractedwith hexanes (2×20 ml). The combined organic extracts are washed withhydrochloric acid (3N, 2×20 ml), water (1×10 ml), saturated sodiumbicarbonate (2×10 ml) and saline (1×10 ml) and dried over magnesiumsulfate. Suction filtration and concentration under reduced pressuregives the title compound, NMR (CDCl₃) δ1.78 and 3.6; CMR (CDCl₃) 827.99, 39.98, 53.12 and 177.62.

Example 103 4-(Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-2,6-purine-dione (XXVI, Steps Y and Z)

[0415]4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (VII, Example 83, 0.500 g) is dissolved in THF (10 ml)and placed under nitrogen. At 25° C., lithium borohydride (0.052 g) isadded and the mixture is stirred at reflux for 2 hours. The solvent isremoved under reduced pressure. To the crude product is added potassiumhydroxide (1 M, 3.57 ml) and isopropanol (4 ml). The mixture is broughtto reflux for 1 hour to give the title compound.

Example 1043-14-(2,6Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid (XII, Steps AA and BB)

[0416]4-(2,6Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde(XI, Example 9, 0.490 g, 1.32 mmol) is added to a mixture of malonicacid (0.275 g, 2.64 mmol), pyridine (2 ml), and piperidine (1 drop). Themixture is heated to 100° for 16 hours. Four additional equivalents ofmalonic acid are added and heating continued for another 16 hours untilconsumption of aldehyde ceases, to give the title compound.

Example 1053-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid ethyl ester (XXVIII, XII, Steps CC and DD)

[0417]cis/trans-3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]acrylicacid ethyl ester (XII) is obtained by an aldol reaction between aldehyde(XI) (1 equivalent) and ethyl acetate (4.7 equivalents) in the presenceof a strong base such as sodium ethoxide (1.2 equivalents).

Example 106 Methanesulfonic acid4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethylester (XL)

[0418] To a mixture of8-(4-hydroxymethylbicyclo[2.2.2]oct-1-yl)-I,3-dipropyl-3,7-dihydropurine-2,6-dione(X, Example 86) in pyridine at 0° is added methanesulfonyl chloride (1.2equivalents) in pyridine. The mixture is stirred at 0° until completeconversion is achieved and then the solvent removed under reducedpressure.

Example 1072-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]-malonicacid dimethyl ester (XLI)

[0419] Methanesulfonic acid4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethylester (XL, Example 106) is reacted with the anion of dimethyl malonate(formed from the reaction of 1 equivalent of dimethyl malonate with 1.25equivalents of sodium hydride or similar base in THF) at 20-25° givesthe title compound.

Example 1083-[4-(2,6Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid methyl ester (XXXV)

[0420] Hydrolysis of2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]malonicacid dimethyl ester (XLI, Example 107) with hydroxide at elevatedtemperature gives the title compound.

Example 109 Bicyclo[2.2.21octane-1,4-dicarboxylic acid dimethyl ester(III)

[0421] A mixture ofcis/trans-1-(2-chloroethyl)-cyclohexane-1,4-dicarboxylic acid dimethylester (I, 7.63 mmol, 2.00 g), sodium iodide (8.39 mmol, 1.26 g) and THF(20 ml) are stirred and refluxed 6 hr. The mixture is cooled to 20-250,TMU (30.52 mmol, 3.65 ml) is added and the mixture cooled to −78° C. Tothe cold mixture is added a solution of LDA (from 1.28 mldiisoproylamine and 5.25 ml 1.6 M n-butyllithium) in THF (11 ml). Thereaction is stirred with gradual warming to 20-25° C. Hydrochloric acid(3N, 20 ml) is added and briskly stirred 10 min. The THF is removedunder reduced pressure and the resulting aqueous residue is extractedwith hexanes (2×20 ml). The combined organic extracts are washed withhydrochloric acid (3N, 2×20 ml), water (1×10 ml), saturated sodiumbicarbonate (2×10 ml) and saline (1×10 ml) and dried over magnesiumsulfate. Suction filtration and concentration under reduced pressuregives the title compound.

Example 110 Bicyclo[2.2.2]octane-1,4-dicarboxylic acid dimethyl ester(III, Step TT)

[0422] To a stirred solution of diisopropylamine (84.5 ml, 600 mmol) inTHF (anhydrous, 700 ml) cooled to −30° C. under nitrogen is addedn-butyl lithium (2.5 M in hexane, 220 ml, 550 mmol) by a syringe. Themisture is stirred for 30 min at −30° C. and then cooled to −78° C. HMPA(360 ml, 4 equivalents, 2 mol) is added by a syringe and a dolution ofdimethyl cyclohexane-1,4-dicarboxylate (100 g, 500 mmol) in THF(anhydrous, 100 ml is added by a syringe subsequently. The mixture isstirred for an additional 40 min. Then 1-bromo-2-chloroethane (41.5 ml,500 mmol) is added and the mixture stirred at −78° C. for an additional20 min. The cold bath is removed and stirring is continued for 1 hr. Thereaction mixture is cooled back to −78° and a mixture of HMPA (360 ml, 4eq, 2 mol) in THF 600 ml) is added. By cannula, freshly prepared LDA(200 ml of n-butyl lithium, 2.5 M in hexane, 500 mmol is added todiisopropylamine (78 ml, 556 mmol) in THF (anhydrous, 700 ml)) istransferred into the reaction mixture at −78°. The reaction mixture isstirred at −78° for 1.33 hr followed by removal of the cooling bath andadditional stirring for 5-6 hr. The mixture is quenched with saturatedaqueous ammonium chloride (400 ml) and concentrated under reducedpressure at 35° to remove the THF. The residue is diluted with water(800 ml) and extracted with hexance (3×600 ml). The combined extractsare washed with saline (700 ml) and dried over sodium sulfate. Using abath temperature of 35° the solvents are are removed under reducedpressure to give a residue. The residue is stirred with hexane (50 ml)at 20-25° for 0.5 hr. The resulting suspension is cooled to 0° for 2 hrand filtered to give the title compound.

Example 111 Assay Methodology

[0423] One hundred eighty-four xanthine derivatives were prepared,having the structures indicated in FIG. 2. For some of these compounds,the K_(i) values for rat and human adenosine A₁ receptors and for humanadenosine A_(2a) receptors were determined according to the followingbinding assay protocol. The ratio A_(2a)/A₁ was also calculated.

Materials

[0424] Adenosine deaminase and HEPES were purchased from Sigma (St.Louis, Mo.). Ham's F-12 cell culture medium and fetal bovine serum werepurchased from GIBCO Life Technologies (Gaithersburg, Md.). AntibioticG-418, Falcon 150 mM culture plates and Costar 12-well culture plateswere purchased from Fisher (Pittsburgh, Pa.). [³H]CPX was purchased fromDuPont-New England Nuclear Research Products (Boston, Mass.).Penicillin/streptomycin antibiotic mixture was purchased from Mediatech(Washington, D.C.). The composition of HEPES-buffered Hank's solutionwas: 130 MM NaCl, 5.0 mM Cl, 1.5 mM CaCl₂, 0.41 mM MgSO₄, 0.49 mMNa₂HPO₄, 0.44 mM KH₂PO₄, 5.6 mM dextrose, and 5 mM HEPES (pH 7.4).

Membrane preparation

[0425] Rat A₁ Receptor: Membranes were prepared from rat cerebral cortexisolated from freshly euthanized rats. Tissues were homogenized inbuffer A (10 mM EDTA, 10 mM Na-HEPES, pH 7.4) supplemented with proteaseinhibitors (10 μg/ml benzamidine, 100 μM PMSF, and 2 μg/ml each ofaprotinin, pepstatin and leupeptin), and centrifuged at 20,000×g for 20min. Pellets were resuspended and washed twice with buffer HE (10 mMNa-HEPES, 1 mM EDTA, pH 7.4, plus protease inhibitors). Final pelletswere resuspended in buffer HE, supplemented with 10% (w/v) sucrose andprotease inhibitors, and frozen in aliquots at −80° C. Proteinconcentrations were measured using BCA protein assay kit (Pierce).

[0426] Human A₁ Receptor: Human A1 adenosine receptor cDNA was obtainedby RT-PCR and subcloned into pcDNA3. 1 (Invitrogen). Stable transfectionof CHO-K1 cells was performed using LIPOFECTAMINE-PLUS (GIBCO-BRL) andcolonies were selected in 1 mg/ml G418, and screened using radioligandbinding assays. For membrane preparations, CHO-K1 cells growing asmonolayers in complete media (F12+10%FCS+1 mg/ml G418) were washed inPBS and harvested in buffer A supplemented with protease inhibitors.Cells were homogenized, centrifuged, and washed twice with buffer HE asdescribed above. Final pellets were stored in aliquots at −80° C.

Radioligand Binding Assays

[0427] Membranes (50 μg membrane protein for rat A1ARs, and 25 μg ofCHO-K1 membrane protein for human A1ARs), radioligands and varyingconcentrations of competing ligands were incubated in triplicates in 0.1ml buffer HE plus 2 units/ml adenosine deaminase for 2.5 h at 21° C.Radioligand [³H]DPCPX (112 Ci/mmol from NEN, final concentration:1 nM)was used for competition binding assays on A₁ARs. Nonspecific bindingwas measured in the presence of 10 μM BG9719. Binding assays wereterminated by filtration over Whatman GF/C glass fiber filters using aBRANDEL cell harvester. Filters were rinsed three times with 3-4 mlice-cold 10 mM Tris-HCl, pH 7.4 and 5 mM MgCl₂ at 4° C. Filter paper wastransferred to a vial, and 3 ml of scintillation cocktail ScintiVerseII(Fisher)was added. Radioactivity was counted in a Wallac β-counter.

Analysis of Binding Data

[0428] For K_(I) Determinations: Competition binding data were fit to asingle-site binding model and plotted using Prizm GraphPad.Cheng-Prusoff equation K_(I)=IC₅₀/(1+[I]/K_(D)) was used to calculateK_(I) values from IC₅₀ values, where K_(I) is the affinity constant forthe competing ligand, [I] is the concentration of the free radioligand,and K_(D) is the affinity constant for the radioligand.

[0429] For % Binding: For one-point binding assays, data were presentedas % of total specific binding at 1 μM of competing compound: % oftotal=100* (Specific binding with 1 μM of competing compound/totalspecific binding).

Results

[0430] All of the compounds tested exhibited rat A₁ K_(i) values between0.6 and 433.8 nM, human A₁ K_(i) values between 1.6 and 1000 nM, andhuman A_(2a)K_(i) values between 132 and 49930 nM. All of the compoundshad A_(2a)/A₁ ratios greater than 10, most greater than 20, many greaterthan 50, and some greater than 100. At least one compound had aA_(2a)/A₁ ratio greater than 1000.

Example 112 Alternative Assay Methodology Materials See Example 111 CellCulture

[0431] CHO cells stably expressing the recombinant human A₁AdoR(CHO:A₁AdoR cells) were prepared as described (Kollias-Barker et al., J.Pharma. Exp. Ther. 281(2), 761, 1997) and cultured as for CHO:Wildcells. CHO cells were cultured as monolayers on plastic dishes in Ham'sF-12 medium supplemented with 10% fetal bovine serum, 100 U penicillin Gand 100 μg streptomycin in a humidified atmosphere of 5% CO₂/95% air at37° C. The density of [³H]CPX binding sites in CHO cells was 26±2 (n=4)finol/mg protein. Cells were subcultured twice weekly after detachmentusing 1 mM EDTA in Ca²⁺—Mg²⁺-free HEPES-buffered Hank's solution. Threedifferent clones of CHO:A₁AdoR cells were used for experiments, and allresults were confirmed with cells from two or three clones. The densityof A₁AdoRs in these cells was 4000-8000 fmol/mg protein, as determinedby assay of (³H]CPX specific binding.

Radioligand Binding

[0432] CHO cells grown on 150 mm culture dishes were rinsed withHEPES-buffered Hank's solution, then removed with a cell scraper andhomogenized in ice-cold 50 mM Tris-HCl, pH 7.4. Cell membranes werepelleted by centrifugation of the cell homogenate at 48,000×g for 15minutes. The membrane pellet was washed twice by resuspension in freshbuffer and centrifugation. The final pellet was resuspended in a smallvolume of 50 mM Tris-HCl, pH 7.4, and stored in aliquots of 1 ml at −80°C. until used for assays.

[0433] To determine the density of A₁AdoRs in CHO cell membranes, 100 μ;aliquots of membranes (5 μg protein) were incubated for 2 hours at 25°C. with 0.15-20 nM [³H]CPX and adenosine deaminase (2 U/ml) in 100 μl of50 mM Tris-HCl, pH 7.4. Incubations were terminated by dilution with 4ml of ice-cold 50 mM Tris-HCl buffer and immediate collection ofmembranes onto glass-fiber filters (Schleicher and Schuell, Keene, N.H.)by vacuum filtration (Brandel, Gaithersburg, Md.). Filters were washedquickly three times with ice-cold buffer to remove unbound radioligand.Filter discs containing trapped membranes bound radioligand were placedin 4 ml of Scintiverse BD (Fisher), and the radioactivity was quantifiedusing a liquid scintillation counter. To determine nonspecific bindingof [³H]CPX, membranes were incubated as described above and 10 μM CPTwas added to the incubation buffer. Nonspecific binding was defined as[³H]CPX bound in the presence of 10 μM CPT. Specific binding of theradioligand to the A₁AdoR was determined by subtracting nonspecificbinding from total binding. Nonspecific binding was found to increaselinearly with an increase of [³H]CPX concentration. Triplicate assayswere done at each tested concentration of [³H]CPX.

[0434] To determine the affinities of antagonists of A₁AdoRs for thehuman recombinant A₁AdoR expressed in CHO cells, binding of 2 nM [³H]CPXin the presence of increasing concentrations of antagonist was measured.Aliquots of CHO cell membranes (100 μl: 5 μg protein), [³H]CPX,antagonist (0.1 nM-100 μM), and adenosine deaminase (2 U/ml) wereincubated for 3 hours at 25° C. in 200 μl of 50 mM Tris-HCl buffer (pH7.4). Assays were terminated as described above.

Data Analysis

[0435] Binding parameters (i.e., B_(max), K_(d), IC₅₀, K_(i), and Hillcoefficients) were determined using the radioligand binding analysisprogram LIGAND 4.0 (Elsevier-Biosoft).

Other Embodiments

[0436] It is to be understood that while the invention has beendescribed in conjunction with the detailed description thereof, theforegoing description is intended to illustrate and not limit the scopeof the invention, which is defined by the scope of the appended claims.Other aspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A compound comprising the formula:

wherein R₁ and R₂ are independently selected from the group consistingof: a) hydrogen; b) alkyl, alkenyl of not less than 3 carbons, oralkynyl of not less than 3 carbons; wherein said alkyl, alkenyl, oralkynyl is either unsubstituted or functionalized with one or moresubstituents selected from the group consisting of hydroxy, alkoxy,amino, alkylamino, dialkylamino, heterocyclyl, acylamino,alkylsulfonylamino, and heterocyclylcarbonylamino; and c) aryl orsubstituted aryl; R₃ is selected from the group consisting of: (a) abicyclic, tricyclic or pentacyclic group selected from the groupconsisting of:

wherein the bicyclic or tricyclic group is either unsubstituted orfunctionalized with one or more substitents selected from the groupconsisting of: (a) alkyl, alkenyl, and alkynyl; wherein each alkyl,alkenyl, or alkynyl group is either unsubstituted or functionalized withone or more substituents selected from the group consisting of(amino)(R₅)acylhydrazinylcarbonyl, (amino)(R₅)acyloxycarboxy,(hydroxy)(carboalkoxy)alkylcarbamoyl, acyloxy, aldehydo,alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylaminoalkylamino,alkylphosphono, alkylsulfonylamino, carbamoyl, R₅, R₅-alkoxy,R₅-alkylamino, cyano, cyanoalkylcarbamoyl, cycloalkylamino,dialkylamino, dialkylaminoalkylamino, dialkylphosphono,haloalkylsulfonylamino, heterocyclylalkylamino, heterocyclylcarbamoyl,hydroxy, hydroxyalkylsulfonylamino, oximino, phosphono, substitutedaralkylamino, substituted arylcarboxyalkoxycarbonyl, substitutedheteroarylsulfonylamino, substituted heterocyclyl, thiocarbamoyl, andtrifluoromethyl; and (b) (alkoxycarbonyl)aralkylcarbamoyl, aldehydo,alkenoxy, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylcarbamoyl,alkoxycarbonylamino, alkylsulfonylamino, alkylsulfonyloxy, amino,aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl,aminoalkylheterocyclylalkylcarbamoyl,aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl,aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino,arylsulfonyloxy, carbamoyl, carbonyl, —R₅, R₅-alkoxy,R₅-alkyl(alkyl)amino, R₅-alkylalkylcarbamoyl, R₅-alkylamino,R₅-alkylcarbamoyl, R₅-alkylsulfonyl, R₅-alkylsulfonylamino,R₅-alkylthio, R₅-heterocyclylcarbonyl, cyano, cycloalkylamino,dialkylaminoalkylcarbamoyl, halogen, heterocyclyl,heterocyclylalkylamino, hydroxy, oximino, phosphate, substitutedaralkylamino, substituted heterocyclyl, substitutedheterocyclylsulfonylamino, sulfoxyacylamino, and thiocarbamoyl; and (b)the tricyclic group:

wherein the tricyclic group is functionalized with one or moresubstituents selected from the group consisting of: (a) alkyl, alkenyl,and alkynyl; wherein each alkyl, alkenyl, or alkynyl group is eitherunsubstituted or functionalized with one or more substituents selectedfrom the group consisting of (amino)(R₅)acylhydrazinylcarbonyl,(amino)(R₅)acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl,acyloxy, aldehydo, alkenylsulfonylamino, alkoxy, alkoxycarbonyl,alkylaminoalkylamino, alkylphosphono, alkylsulfonylamino, carbamoyl, R₅,R₅-alkoxy, R₅-alkylamino, cyano, cyanoalkylcarbamoyl, cycloalkylamino,dialkylamino, dialkylaminoalkylamino, dialkylphosphono,haloalkylsulfonylamino, heterocyclylalkylamino, heterocyclylcarbamoyl,hydroxy, hydroxyalkylsulfonylamino, oximino, phosphono, substitutedaralkylamino, substituted arylcarboxyalkoxycarbonyl, substitutedheteroarylsulfonylamino, substituted heterocyclyl, thiocarbamoyl, andtrifluoromethyl; and (b) (alkoxycarbonyl)aralkylcarbamoyl, aldehydo,alkenoxy, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylcarbamoyl,alkoxycarbonylamino, alkylsulfonylamino, alkylsulfonyloxy, amino,aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl,aminoalkylheterocyclylalkylcarbamoyl,aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl,aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino,arylsulfonyloxy, carbamoyl, carbonyl, —R₅, R₅-alkoxy,R₅-alkyl(alkyl)amino, R₅-alkylalkylcarbamoyl, R₅-alkylamino,R₅-alkylcarbamoyl, R₅-alkylsulfonyl, R₅-alkylsulfonylamino,R₅-alkylthio, R₅-heterocyclylcarbonyl, cyano, cycloalkylamino,dialkylaminoalkylcarbamoyl, halogen, heterocyclyl,heterocyclylalkylamino, oximino, phosphate, substituted aralkylamino,substituted heterocyclyl, substituted heterocyclylsulfonylamino,sulfoxyacylamino, and thiocarbamoyl; R₄ is selected from the groupconsisting of hydrogen, C₁₋₄-alkyl, C₁₋₄-alkyl-CO₂H, and phenyl, whereinthe C₁₋₄-alkyl, C₁₋₄-alkyl-CO₂H, and phenyl groups are eitherunsubstituted or functionalized with one to three substituents selectedfrom the group consisting of halogen, —OH, —OMe, —NH₂, NO₂, benzyl, andbenzyl functionalized with one to three substituents selected from thegroup consisting of halogen, —OH, —OMe, —NH₂, and —NO₂; R₅ is selectedfrom the group consisting of —CH₂COOH, —C(CF₃)₂OH, —CONHNHSO₂CF₃,—CONHOR₄, —CONHSO₂R₄, —CONHSO₂NHR₄, —C(OH)R₄PO₃H₂, —NHCOCF₃,—NHCONHSO₂R₄, NHPO₃H₂, —NHSO₂R₄, —NHSO₂NHCOR₄, —OPO₃H₂, —OSO₃H,—PO(OH)R₄, —PO₃H₂, —SO₃H, —SO₂NHR₄, —SO₃NHCOR₄, —SO₃NHCONHCO₂R₄, and thefollowing:

 X₁ and X₂ are independently selected from the group consisting of O andS;  Z is selected from the group consisting of a single bond, —O—,—(CH₂)₁₋₃—, —O(CH₂)₁₋₂—, —CH₂OCH₂—, —(CH₂)₁₋₂O—, —CH═CHCH₂—, —CH═CH—,and —CH₂CH═CH—; and  R₆ is selected from the group consisting ofhydrogen, alkyl, acyl, alkylsufonyl, aralkyl, substituted aralkyl,substituted alkyl, and heterocyclyl.
 2. The compound of claim 1, whereinthe compound is in a form selected from the group consisting of anachiral compound, a racemate, an optically active compound, a purediastereomer, a mixture of diastereomers, and a pharmacologicallyacceptable addition salt.
 3. The compound of claim 1, wherein R₁ and R₂are each alkyl groups.
 4. The compound of claim 1, wherein R₁ and R₂ areeach n-propyl.
 5. The compound of claim 1, wherein R₁ is n-propyl and R₃is selected from the group consisting of aralkyl substituted with —OH,—OMe, or -halogen; methyl; and 3-hydroxypropyl.
 6. The compound of claim4, wherein Z is a single bond.
 7. The compound of claim 6, wherein R₃is:

and wherein R₃ is either unsubstituted or functionalized with one ormore substituents selected from the group consisting of hydroxy, R₅—,and R₅-alkenyl.
 8. The compound of claim 7, wherein the compound is5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylic acid.
 9. The compound of claim 7, wherein thecompound is8-(4-Hydroxy-bicyclo-[3.2.1]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.10. The compound of claim 7, wherein the compound is5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-2-carboxylicacid.
 11. The compound of claim 6, wherein R₃ is

and wherein R₃ is either unsubstituted or functionalized with one ormore substituents selected from the group consisting of hydroxy,R₅-alkyl, —R₅, R₅-alkenyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkenyl, hydroxyalkyl, aldehydo, alkoxyalkyl, R₅-alkoxy,phosphate, R₅-alkylcarbamoyl, and R₅-alkyl(alkyl)carbamoyl.
 12. Thecompound of claim 11, wherein the compound is8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.13. The compound of claim 11, wherein the compound is4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid.
 14. The compound of claim 11, wherein the compound is4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde.15. The compound of claim 11, wherein the compound is4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester.
 16. The compound of claim 11, wherein the compound is3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid methyl ester.
 17. The compound of claim 11, wherein the compound is3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid methyl ester.
 18. The compound of claim 11, wherein the compound is3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylicacid.
 19. The compound of claim 11, wherein the compound is3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionicacid.
 20. The compound of claim 11, wherein the compound is4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-butyricacid.
 21. The compound of claim 11, wherein the compound is Phosphoricacidmono-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]ester.22. The compound of claim 11, wherein the compound is{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-methyl-amino}-aceticacid.
 23. The compound of claim 11, wherein the compound is{[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-aceticacid.
 24. The compound of claim 11, wherein the compound is3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid.
 25. The compound of claim 11, wherein the compound is3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid methyl ester.
 26. The compound of claim 11, wherein the compound is3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionicacid t-butyl ester.
 27. The compound of claim 11, wherein the compoundis3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-2-methyl-propionicacid.
 28. The compound of claim 6 wherein R₃ is

and wherein R₃ is either unsubstituted or functionalized with one ormore substituents selected from the group consisting of R₅-alkyl, —R₅,R₅-alkenyl, alkoxycarbonyl, alkoxycarbonylalkenyl, hydroxyalkyl,aldehydo, and hydroxy.
 29. The compound of claim 28, wherein thecompound is6-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cubane-3-carboxylicacid.
 30. The compound of claim 28, wherein the compound is8-(6-Hydroxymethyl-cuban-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.31. The compound of claim 28, wherein the compound is3-[6-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cuban-3-yl]-acrylicacid.
 32. The compound of claim 6 wherein R₃ is

and wherein R₃ is either unsubstituted or functionalized with one ormore substituents selected from the group consisting of R₅-alkyl, —R₅,R₅-alkenyl, R₅-alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl,hydroxyalkyl, aldehydo, and hydroxy.
 33. The compound of claim 32,wherein the compound is[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]non-1-yloxy]-aceticacid.
 34. The compound of claim 32, wherein the compound is8-(5-Hydroxy-bicyclo[3.2.2]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.35. The compound of claim 32, wherein the compound is5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]nonane-1-carboxylicacid.
 36. The compound of claim 6 wherein R₃ is

and wherein R₃ is either unsubstituted or functionalized with one ormore substituents selected from the group consisting of hydroxy,R₅-alkoxy, R₅-alkenyl, alkoxycarbonyl, and carbonyl.
 37. The compound ofclaim 36, wherein the compound is8-(4-Hydroxy-7-methyl-2,6-dioxa-bicyclo[3.3.1]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
 38. The compound of claim 36,wherein the compound is[1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-7-methyl-2,6-dioxa-bicyclo[3.3.1]non-4-yloxy]-acetic acid.
 39. A medicament composition comprisinga compound of claim 1 together with a suitable excipient.
 40. A methodof treating a subject suffering from a condition characterized by anelevated adenosine concentration and/or increased sensitivity toadenosine, the method comprising administering to the subject aneffective adenosine antagonizing amount of a compound of claim
 1. 41.The method of claim 40, wherein the condition is selected from the groupconsisting of cardiac and circulatory disorders, degenerative disordersof the central nervous system, respiratory disorders, diseases for whichdiuretic treatment is indicated, Parkinson's disease, depression,traumatic brain damage, post-stroke neurological deficit, respiratorydepression, neonatal brain trauma, dyslexia, hyperactivity, cysticfibrosis, cirrhotic ascites, neonatal apnea, renal failure, diabetes,asthma, and edematous conditions.
 42. The method of claim 40, whereinthe condition is congestive heart failure or renal dysfunction.
 43. Amethod of making 8-substituted xanthines comprising the steps of: a)obtaining a N7, C8-dihydroxanthine; b) protecting the N7 position of thexanthine; c) deprotonating the C8 position with strong base to generatean anion; d) trapping the anion with a carboxyl, carbonyl, aldehyde, orketone compound; and e) deprotecting the protected N7 position to obtainan 8-substituted xanthine.